Amino acid derivatives and absorbable polymers therefrom

ABSTRACT

The present invention relates to the discovery of new class of hydrolysable amino acid derivatives and absorbable polyester amides, polyamides, polyepoxides, polyureas and polyurethanes prepared therefrom. The resultant absorbable polymers are useful for drug delivery, tissue engineering, tissue adhesives, adhesion prevention, bone wax formulations, medical device coatings, stents, stent coatings, highly porous foams, reticulated foams, wound care, cardiovascular applications, orthopedic devices, surface modifying agents and other implantable medical devices. In addition, these absorbable polymers should have a controlled degradation profile.

This application claims a right of priority to U.S. Ser. No. 61/441,983,filed Feb. 11, 2011. This priority filing is incorporated herein in itsentirety.

The present invention relates to the discovery of new class ofhydrolysable amino acid derivatives and absorbable polyester amides,polyamides, polyepoxides, polyureas and polyurethanes preparedtherefrom. The resultant absorbable polymers are useful for drugdelivery, tissue engineering, tissue adhesives, adhesion prevention,bone wax formulations, medical device coatings, stents, stent coatings,foams, highly porous foams, reticulated foams, wound care,cardiovascular applications, orthopedic devices, surface modifyingagents and other implantable medical devices. In addition, theseabsorbable polymers should have a controlled degradation profile.

Amino acids are the “building blocks” of the body. Besides buildingcells and repairing tissue, they form antibodies to combat invadingbacteria & viruses; they are part of the enzyme & hormonal system; theybuild nucleoproteins (RNA & DNA); they carry oxygen throughout the bodyand participate in muscle activity. When a protein is broken down bydigestion the result is 22 known amino acids. Eight are essential(cannot be manufactured by the body) the rest are non-essential (can bemanufactured by the body with proper nutrition). Tyrosine is one of thenon-essential amino acid. Tyrosine transmits nerve impulses to thebrain; helps overcome depression; improves memory; increases mentalalertness; and promotes the healthy functioning of the thyroid, adrenal,and pituitary glands.

U.S. Pat. No. 5,099,060 describes diphenolic monomers based on3-(4-hydroxyphenyl) propionic acid and L-tyrosine alkyl esters(desaminotyrosyl-tyrosine alkyl esters). Subsequent related patentsinvolve variations of this basic monomer structure. These monomers,although useful in many applications, have several limitations. Themonomers are insoluble in water, and therefore the polymers made fromthem are not readily resorbable. In other words, the previouslydescribed polymers prepared from the previously describedwater-insoluble monomers will not have any weight loss while thedegradation of the polymer backbone results in the loss of mechanicalstrength and reduction in the polymer molecular weight. The monomersalso provide two phenolic hydroxyl groups, limiting the resultingpolymers to be fully aromatic backbone structures, which may lead togood mechanical strength but slow degradation rate.

Poly(hydroxy acids), such as poly(glycolic acid) (PGA), poly(lacticacid) (PLA) and their copolymers are certainly the most widelyinvestigated synthetic, degradable polymers due to their establishedrecord of safety and FDA approval. Poly(amino acids) derived fromnaturally occurring α-L-amino acids form another major group ofdegradable polymers. Despite their apparent potential as biomaterials,poly(amino acids) have actually found few practical applications. Amajor problem is that most of the poly(amino acids) are highlyintractable (e.g., non-processible), which limits their utility.

Although several copolymers of hydroxy acids and amino acids have beenprepared and evaluated from a biological perspective, theirinvestigation as biomaterials has been rather limited. Helder et al., J.Biomed. Mater. Res., (24), 1005-1020 (1990) discloses the synthesis ofglycine and DL-lactic acid copolymers and the resulting in vitro and invivo degradation. The elegant synthesis of a copolymer derived fromlactic acid and lysine was reported by Barrera et al., Macromolecules,(28), 425-432 (1995). The lysine residue was utilized to chemicallyattach a cell-adhesion promoting peptide to the copolymer. Otherpolymers of amino acids and hydroxy acids are disclosed by U.S. Pat. No.3,773,737.

Polymers that are designed to degrade under physiological conditions arereferred to as absorbable polymers. These polymers are sometimes alsoreferred to as biodegradable, bioerodible, bioabsorbable, absorbable orhydrolyzable polymers. Synthetic absorbable polymers are generallyclassified into polyesters, polyorthoesters, polyanhydrides,polyesteramides, polyoxaesters.

Absorbable polymers are increasingly used in a wide range of biomedicalapplications including tissue engineering scaffolds, stents, stentcoatings, foams, highly porous foams, reticulated foams, and adhesionprevention barriers. This increased utilization is, in part, a functionof the transient nature of these polymers when used as biomedicalimplants or drug carriers. Medical devices made from bioabsorbablepolymers can mitigate the inevitable and usually negative physiologicresponses (e.g., fibrous encapsulation), which limit long-term devicesuccess. Hence, an array of absorbable polymers have been developed andstudied in various biomedical applications. While significant researchand development activity has been carried out on absorbable polymers,such polymers may suffer from performance deficiencies which aretypically not fully recognized until new applications are identified andin-use testing has been carried out. As more uses for these materialsare envisioned, an increased demand for absorbable polymers with new andimproved properties targeted to address performance deficiencies may beexpected to follow.

Of the synthetic absorbable polymers, polyesters find numerousapplications in medical, surgical and controlled delivery applicationsand are the key components of a majority of absorbable medical devices,ranging from sutures, staples, orthopedic screws and implantablesurgical devices to tissue engineering scaffolds.

In addition to polyesters, segmented polyurethane elastomers have alsoenjoyed wide use as biomaterials generally due to their excellentmechanical properties and desirable chemical versatility. Whilepolyurethane polymers have certain useful properties, shaped articlesbased on these polymers are not typically absorbable and may thereforebe unacceptable in circumstances that require bioabsorption. Forexample, certain biomedical applications, such as surgical devicesincluding but not limited to monofilament and multifilament sutures,films, sheets, plates, clips, staples, pins, screws, stents, stentcoatings, and the like, generally require the use of a material that isabsorbable. Hence, the vast majority of research devoted to thedevelopment of biomedical polyurethanes has focused on long-termapplications such as vascular grafts and pacemaker lead insulators.

Despite progress in the general development of polyurethanes and similarpolymers for use in biomedical applications, relatively little researchhave been directed to developing absorbable polyurethanes for temporary,rather than longer-term implantation. See Fuller et al., U.S. Pat. No.4,829,099; Beckmann et al., U.S. Patent Publication Nos. 2005/0013793,2004/0170597, and 2007/0014755; Bruin et al., PCT Publication No. WO95/26762; Woodhouse et al., U.S. Pat. No. 6,221,997; Cohn et al., U.S.Pat. No. 4,826,945, which generally discuss recent advances made in thefield of absorbable polyurethanes.

Subsequent work by Bruin et al., PCT No. WO 95/26762, discloses thesynthesis of crosslinked polyurethane networks incorporating lactide orglycolide and ε-caprolactone joined by a lysine-based diisocyanate.Bruin discloses that these polymers display good elastomeric propertiesand degrade within about 26 weeks in vitro and about 12 weeks in vivo(subcutaneous implantation in guinea pigs). Despite their discloseddesirable flexibility and degradation characteristics, these highlycrosslinked polymers are not extensively used in some biomedicalapplications because in some cases they cannot be readily processed intosurgical articles, for example, using standard techniques such assolution casting or melt processing, as is the case for the more typicallinear, segmented polyurethanes.

Cohn et al., EP 295055 discloses a series of elastomericpolyester-polyether -polyurethane block copolymers intended for use assurgical articles. However, these polymers may be relatively stiff andmay have low tensile strength, which may preclude their use aselastomeric biomaterials. Beckmann et al., U.S. Patent Publication No.2005/0013793 describes polyurethane-based biodegradable adhesives frommulti-isocyanate functional molecules and multifunctional precursormolecules with terminal groups selected from hydroxyl and amino groups.Woodhouse et al. discloses absorbable polyurethanes derived from aminoacids. However, all these absorbable polyurethanes may suffer from oneor more of the following drawbacks: (a) the very slow rate of formationof polyurethane which may be attributed to the low reactivity of thepolyisocyanates, and (b) the lack of tunable physical and/or mechanicalproperties and/or controllable hydrolytic degradation profiles forbiodegradable polyisocyanates or absorbable polyurethanes derivedtherefrom.

Bezwada (U.S. Patent Application Publication Nos. 20060188547,20090292029, European Patent Publication No. EP 1937182 and WO2007030464) discloses polyurethanes, the corresponding polyisocyanates,and preparations of their manufacture and use wherein the polyurethanesand/or polyisocyanates were reported to be absorbable.

Despite advancements in the art of producing polymeric materials andmethods for making polymers suitable for use in drug delivery, tissueadhesives, adhesion prevention barrier, foams, highly porous foams,reticulated foams, bone wax formulations, stents, stent coatings,scaffolds, films, molded devices, and similar surgical articles,presently available polymers generally lack adequate performanceproperties desirable in surgical articles, for example, those related tobioabsorption, flex fatigue life, strength in use, flexibility and/ordurability. Thus, there continues to be a need for new devices andpolymers having tunable physical and/or biological properties, so thatmedical devices and surgical articles having a variety of end uses canbe prepared. The present invention is directed, among other things, toabsorbable drug delivery systems, tissue adhesives, adhesion preventionbarrier, foams, highly porous foams, reticulated foams, stents, bone waxformulations, coatings including stent coatings, tissue engineeringscaffolds, films, molded devices and/or flexible films with tunablephysical and biological properties, and improving the processability ofpolyurethanes during molding and extrusion, surface properties offinished products.

SUMMARY OF THE INVENTION

Accordingly, the present invention is directed, in part, towardsdeveloping amino acid derivatives, and amine derivatives includingisocyanates, amide diacids that can provide novel absorbable materialsthat are useful for drug delivery, tissue engineering, tissue adhesives,adhesion prevention, foams, highly porous foams, reticulated foams,stents, stent coatings, medical device coaings, bone wax formulationsand other implantable medical devices.

In certain embodiments, the invention provides novel hydrolysable aminesand isocyanates derived from nitrophenyl alanine and 3-nitrotyrosinethat can provide polyamides, polyester amides, polyurethanes and thelike which are absorbable and biocompatible. In certain embodiments, theinvention provides novel and highly reactive isocyanates that canprovide polyurethanes and other polymers which are absorbable andbiocompatible.

In certain embodiments, the present invention provides novel amines andisocyanates derived from amino acids selected from tyrosine,3-aminotyrosine, 3-chlorotyrosine, 3,5-dibromotyrosine,3,5-diiodotyrosine, homotyrosine, 3-iodotyrosine, 3-nitrotyrosine,2-tyrosine, 3-tyrosine, 4-hydroxy-3-nitrophenylalanine,5-hydroxytryptophan, 3-nitro-4-hydroxyphenylalanine, thyronine,3,4-dihydroxyphenylalanine, 4-hydroxyphenylglycine, 3-aminosalicylicacid; 4-aminosalicylic acid; and 5-aminosalicylic acid.

In certain embodiments, the invention provides diamine derivatives thatcan provide hydrophilic absorbable polyester amides that arebiocompatible for absorbable sutures, staples clips, adhesion preventionbarriers.

In certain embodiments, the invention provides novel polyurethanes,polyesters, polyester amides which are biodegradable and biocompatiblefor tissue engineering, drug delivery, tissue adhesives, adhesionprevention and other implantable medical devices.

In certain embodiments, the invention provides novel hydrolysableisocyanates for use in the formation of polyurethanes and otherpolymers.

In certain embodiments, the invention provides novel hydrolysablebranched isocyanates with pendant long chain alkyl groups that arehydrophobic or pendant long chain PEG that are hydrophilic.

In certain embodiments, the invention provides amino acid derivativeswherein the release of drug and amino acid can be controlled.

In certain embodiments, the present invention provides NO and drugreleasing amino acid derivatives wherein the rate of release of drug andnitric oxide along with the parent amino acid can be controlled.

Briefly stated, the present invention relates to the discovery of a newclass of hydrolysable amines, hydrolysable isocyanates, hydrolysableamides, hydrolysable amide diacids, hydrolysable amino acid-drug, aminoacid-drug-NO monomers and absorbable polyurethanes, polyureas, polyesteramides and polyepoxides and blends thereof prepared therefrom. Theresultant absorbable polymers are useful for drug delivery, tissueengineering, tissue adhesives, adhesion prevention, bone waxformulations, foams, highly porous foams, reticulated foams, stents,stent coatings, medical device coatings, surface modifying agents andother implantable medical devices. In addition, these absorbablepolymers should have a controlled degradation profile.

In another embodiment of the present invention, absorbable polyesters,polyurethanes, polyureas and polyester amides of the present inventioncan be further polymerized with lactone monomers including but notlimited to glycolide, lactide, caprolactone, p-dioxanone, TMC,δ-valerolactone, β-butyrolactone, morpholinedione, pivalolactone,ε-decalactone, 2,5-diketomorpholine and combinations thereof in order tocontrol physical and biological properties.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENT

The present invention relates to the discovery of a new class ofhydrolyzable isocyanates, hydrolysable amides, hydrolysable aminoacid-drug and hydrolysable amino acid-drug-NO and absorbable polyesteramides, polyurethanes, polyepoxides prepared therefrom. The absorbablepolymers that result from polymerization of these absorbableisocyanates, amides, amide diacids are useful for, inter alia, drugdelivery, tissue engineering, tissue adhesives, adhesion prevention,bone wax formulations, medical device coatings, foams, highly porousfoams, reticulated foams, stents and stent coatings and otherimplantable medical devices. In addition, these absorbable polymers areexpected to have a controllable degradation profile.

As employed above and throughout the disclosure, the terms definedbelow, unless otherwise indicated, shall be understood to have thedefined meanings.

As used herein, the term “monomers” includes macromers, unless thecontext clearly indicates otherwise.

As used herein, unless otherwise defined “alkyl” refers to an optionallysubstituted, saturated straight, or branched hydrocarbon moiety havingfrom about 1 to about 20 carbon atoms (and all combinations andsubcombinations of ranges of carbon atoms and specific numbers of carbonatoms therein) (or, where so defined, 1 to about 36 carbons or 2 to 24carbons), or with from about 1 to about 8 carbon atoms, herein referredto as “lower alkyl”, or from about 1 to about 3 carbon atoms, such asmethyl or ethyl. Alkyl groups include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl,2,2-dimethylbutyl, and 2,3-dimethylbutyl.

As used herein, the term “absorbable” refers to those classes ofmaterials that readily hydrolyze and/or enzymatically degrade uponexposure to bodily tissue in a relatively short period of time, thusexperiencing a significant weight loss in that short time period. Arelatively short period of time shall be judged from the context. Forexample, in some contexts, the relatively short period may be two weeksto eight weeks, while in others it may be eight weeks to fifty two weeksor longer. Complete bioabsorption should take place within twelvemonths, or within nine months, or within six months. In this manner, thepolymers derived from isocyanates of the invention may be fabricatedinto medical and surgical devices which are useful for a vast array ofapplications requiring complete or substantially complete absorptionwithin the relatively short time periods set forth herein.

The biological properties of the absorbable polymers of the presentinvention used to form devices or parts thereof, as measured by itsabsorption rate and its breaking strength retention in vivo (BSR), canbe varied to suit the needs of the particular application for which thefabricated medical device or component is intended. This can beconveniently accomplished by varying the ratio of components of thepolymer chosen.

Depending on the formation route selected, these cleavable sites may beregular along the length of the chain extender, thereby giving thesegmented polyurethane or polyester or the like a biodegradability whichis, by some measure, predictable. Biodegradability is influenced by anumber of factors, including crystallinity. The hydrophilicity of thepolymer may also influence the degradability, that is, the extent towhich water is accessible to the polymer matrix. The number of cleavagesites may also influence biodegradability. Generally speaking, thehigher the number of sites, the greater the rate of degradation.Preferably, the cleavable site is an ester site and, more preferably,the cleavable ester site is derived from a hydroxy acid precursor. Thisprovides segmented polyurethanes and polyesters or the like withcleavable sites that may be arranged to be recognizable by enzymes.

The polyester amides disclosed herein may be prepared by reacting amideacid of the present invention with diols in the presence of anorganometallic catalyst at elevated temperatures. The organometalliccatalyst is preferably a tin-based catalyst, e.g. stannous octoate andis present in the monomer mixture at a mole ratio of monomer-to-catalystranging from about 15,000 to about 80,000/1. The polymerization istypically carried out at a temperature ranging from about 120 to about200 degree C., or about 160 to about 190 degree C., until the desiredmolecular weight and viscosity are achieved. The polyurethanes and otherpolymers disclosed herein may be prepared by reacting isocyanates of thepresent invention with branched chain extender or a chain extender andpolyols of the present invention and/or generic polyols includingpolyethylene glycols, polyesterdiols and polyetherdiols. The polyamidesdisclosed herein may be prepared by reacting diamines of the presentinvention with diacids of the present invention and/or generic diacidsincluding polyethylene diacids, polyesterdiacids and polyetherdiacids.The polyepoxides disclosed herein may be prepared by reacting diaminesof the present invention with epoxides.

One of the beneficial properties of the polymers of the presentinvention is that the ester linkages are hydrolytically unstable, andtherefore the polymer is absorbable because it readily breaks down intosmall segments when exposed to moist bodily tissue.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds. Within the context of the present invention, compoundsare stable if they do not degrade significantly prior to their intendeduse under normal conditions. In some instances, compounds of theinvention may be designed or required to be bioabsorbed or biodegradedas part of their intended function. Absorbability and/orbiodegradability, which may be an advantageous property of the presentpolymers, is not intended to mean that the polymeric compound areunstable.

It is believed the chemical formulas and names used herein correctly andaccurately reflect the underlying chemical compounds. However, thenature and value of the present invention does not depend upon thetheoretical correctness of these formulae, in whole or in part. Thus itis understood that the formulas used herein, as well as the chemicalnames attributed to the correspondingly indicated compounds, are notintended to limit the invention in any way, including restricting it toany specific tautomeric form, except where such limit is clearlydefined.

In one embodiment, the present invention introduces hydrolysablearomatic amines of formula A prepared by reacting functionalized aminoacids i.e. amino acids functionalized with safe and biocompatiblemolecules (e.g., glycolic acid, lactic acid, caprolactone, anddioxanone) with aminophenol and amino benzoic acid. Bezwada US PatentPublication Numbers 2008/0057127A1, 2007/0135355A1 and 2009/0098180 A1disclose functionalized amino acids along with their preparation andapplications.

Wherein:

-   Each X is independently selected from:-   —OCH₂CO— (glycolic ester moiety)-   —OCH(CH₃)CO— (lactic ester moiety)-   —OCH₂CH₂OCH₂CO— (dioxanone ester moiety)-   —OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone ester moiety);-   —O(CH₂)_(y)CO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —O(CH2CH2O)_(m)CH2CO—; where m is integer between 2-24 inclusive    (together, the “X Options”);-   And wherein p is independently selected from 0 to 6 inclusive;-   Each X′ is independently selected from:-   —CH₂COO— (glycolic moiety)-   —CH(CH₃)COO— (lactic moiety)-   —CH₂CH₂OCH₂COO— (dioxanone moiety)-   —CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety)-   —(CH2)_(y)COO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —(CH2CH2O)_(m)CH2COO—; where m is integer between 2-24 inclusive    (together, the “X′ Options”); and,-   R is a residue of an amino acid including but not limited to    alanine, asparagine, aspartic acid, gamma amino butyric acid,    glycine, glutamic acid, valine, lysine, isoleucine, leucine,    tyrosine, ornithine, phenylalanine and sarcosine, 3-aminotyrosine,    3-chlorotyrosine, 3,5-dibromotyrosine, 3,5-diiodotyrosine,    homotyrosine, 3-iodotyrosine, 3-nitrotyrosine, 2-tyrosine,    3-tyrosine, 4-hydroxy-3-nitrophenylalanine, 5-hydroxytryptophan,    3-nitro-4-hydroxyphenylalanine, thyronine,    3,4-dihydroxyphenylalanine, 4-hydroxyphenylglycine, 3-aminosalicylic    acid; 4-aminosalicylic acid; and 5-aminosalicylic acid. The phrase    “residue of an amino acid” refers to the chemical constituents of an    amino acid except the amino and carbonyl/carboxylic acid moieties.    These amino and carbonyl/carboxylic acid moieties are shown in the    various structures illustrated herein appropriately adjacent to “R”    or some other label for a residue of an amino acid. In certain    embodiments, the amino acids are naturally occurring amino acids. In    certain embodiments, the amino acids are natural constituents of    mammalian protein, neurotransmitters or natural metabolic    intermediate. In certain embodiments, the amino acids are natural    constituents of mammalian protein.

In the structures shown in this application the aryl groups having anamino (or amino derived group) and a hydroxy (or hydroxy-derived group)or carboxy (or carboxy-derived group are typically illustrated in oneorientation for simplicity (e.g., para), but these can be ortho, meta orpara.

Structures of representative examples of absorbable amines of theformula (A) including but not limited to the following:

In all embodiments herein, preferably one or more occurrences of p is≧1. In certain embodiments of these embodiments, one or more occurrencesof p is ≧2.

In another embodiment, the present invention introduces hydrolysablearomatic isocyanates of formula B derived from hydrolysable amines offormula A

Wherein:

-   Each X is independently selected from the X Options;-   Each X′ is independently selected from the X′ Options; and,-   R is a residue of an amino acid.

Structures of representative examples of absorbable isocyanates of theformula (B) including but not limited to the following:

The present invention also provides biodegradable and biocompatiblepolyamides, polyester amides, polyureas, epoxy resins and polyurethanesderived from hydrolysable amines and isocyanates of formula A and Brespectively. These polymers will have tunable mechanical and hydrolyticdegradation properties and are expected to hydrolyze back to safe andbiocompatible molecules including glycolic acid, lactic acid etc andparent amino acid.

In another embodiment the present invention also introduces hydrolysablearomatic amines of formula C prepared by reacting functionalized aminoacids i.e. amino acids functionalized with safe and biocompatiblemolecules (e.g., glycolic acid, lactic acid, caprolactone, anddioxanone) with aminophenol. Bezwada US Patent Publication Number2008/0057127A1, 2007/0135355A1 and 2009/0098180 A1 disclose thesefunctionalized amino acids along with their preparation andapplications.

Wherein

-   Each X′ is independently selected from the X′ Options;-   p is independently selected from 0 to 6 inclusive; and-   R is a residue of an amino acid.-   These amines of formula C upon hydrolysis will yield safe and    biocompatible molecules along with the parent amino acid. Structures    of representative examples of absorbable amines of the formula (C)    including but not limited to the following:

The present invention also introduces hydrolysable aromatic isocyanatesof formula D

Wherein

-   Each X′ is independently selected from the X Options;-   p is independently selected from 0 to 6 inclusive; and,-   R is a residue of an amino acid.

The isocyanates of formula (D) are expected to have differential rate ofreactivity attributed to the presence of aliphatic and aromaticisocyanate moiety within the same molecule. Hence, these isocyanateswill prove beneficial for forming prepolymers. Structures ofrepresentative examples of absorbable isocyanates of the formula (D)including but not limited to the following:

The present invention also provides absorbable polyamides, polyesteramides, polyepoxides and polyurethanes derived from hydrolysable aminesand isocyanates of formula C and D respectively. These polymers are willhave tunable mechanical and hydrolytic degradation properties and areexpected to hydrolyze back to safe and biocompatible molecules includingglycolic acid, lactic acid etc and amino acid.

In another embodiment the present invention also introduces hydrolysablealiphatic amines of formula E prepared by reacting functionalized aminoacids i.e. amino acids functionalized with safe and biocompatiblemolecules (e.g., glycolic acid, lactic acid, caprolactone, anddioxanone) with a linker molecule.

Wherein:

-   Each X is independently selected from the X Options;-   And wherein p is independently selected from 0 to 6 inclusive;-   Each Y is independently selected from:-   —COCH₂O— (glycolic moiety)-   —COCH(CH₃)O— (lactic moiety)-   —COCH₂OCH₂CH₂O— (dioxanone moiety)-   —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone moiety)-   —CO(CH₂)_(y)O— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —CO(CH₂CH₂O)_(m)CH₂O—; where m is integer between 2-24 inclusive    (together, the “Y Options);-   R is a residue of an amino acid; and-   R′ is a residue of a diol where in R′ is alkyl, aryl or arylalkyl.    (Such residue can be for example a residue of a PEG polyol.)

“Alkyl” with respect to R′ or Rx (see below at formula W) in this andother embodiments means containing a primary (long) chain of 2 up to 24chain atoms (not including H), where in the primary chain —CH₂— groupsmay be substituted with —O—, or —S—. Alkyl and aryl can be substitutedwith lower alkyl group(s) of C1 to C6. In certain embodiments, the alkylof R′ is of long chain of 2 to 6 atoms.

These amines of formula E upon hydrolysis will yield safe andbiocompatible molecules including but not limited to glycolic acid,lactic acid, peg and alcohols along with the parent amino acid.

Structures of representative examples of absorbable amines of theformula (E) including but not limited to the following:

In yet another embodiment, the present invention also introduceshydrolysable isocyanates of Formula F derived from hydrolysable aminesof formula E:

Wherein:

-   Each X is independently selected from the X Options;-   And wherein p is independently selected from 0 to 6 inclusive;-   Each Y is independently selected from the Y Options; and-   R is a residue of an amino acid; and-   R′ is a residue of a diol where in R′ is alkyl, aryl or arylalkyl.

Structures of representative examples of absorbable isocyanates of theformula (F) including but not limited to the following:

The present invention also provides absorbable polyamides, polyesteramides, polyepoxides and polyurethanes derived from hydrolysable aminesand isocyanates of formula E and F respectively. These polymers havetunable mechanical and hydrolytic degradation properties and areexpected to hydrolyze back to safe and biocompatible molecules includingglycolic acid, lactic acid etc and parent amino acid.

In one embodiment, the present invention introduces hydrolysablearomatic amines of formula G prepared by reacting functionalizednitrophenylalanine i.e. nitrophenylalanine functionalized with safe andbiocompatible molecules (e.g. glycolic acid, lactic acid, caprolactone,and dioxanone) with amino benzoic acid. Bezwada US Patent PublicationNumbers 2008/0057127A1, 2007/0135355A1 and 2009/0098180 A1 disclosethese functionalized amino acids along with their preparation andapplications.

Wherein:

-   Each Y is independently selected from the Y Options; and,-   R″ is alkyl, aryl or arylalkyl, or R″ is a biologically active    substance.

A biologically active substance in the context of the present inventionis a substance that can act on a cell, virus, organ or organism,including but not limited to drugs (i.e. pharmaceuticals) or naturalproducts, to create a change in the functioning of the cell, virus,organ or organism. In certain embodiments of the invention, thebiologically active substances are organic molecules having molecularweight of about 600 or less, or to polymeric species such as proteins,nucleic acids, and the like. A biologically active substance can be asubstance used in therapy of an animal, preferably a human. For use inthe invention, a biologically active substance bears, or has afunctional homolog that bears, one or more hydroxyl, amino or carboxylicacid substituents, including functional derivatives such as esters,amides, methyl ethers, glycosides and other derivatives that areapparent to those skilled in the art. Examples of biologically activecompounds that can be used in the present invention include Capsaicin,Vitamin E, Resveratrol and isoflavonoids.

These amines of formula G upon hydrolysis will yield safe andbiocompatible molecules along with the amino acid

Structures of representative examples of absorbable amines of theformula (G) including but not limited to the following:

The present invention also provides hydrolysable isocyanates of generalformula H derived from hydrolysable amines of formula G:

Wherein:

-   Each Y is independently selected from the Y Options;-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   R″ is alkyl, aryl or arylalkyl, or R″ is a biologically active    substance.

Structures of representative examples of absorbable isocyanates of theformula (H) includes the following

The present invention also provides absorbable polyamides, polyesteramides, polyepoxides and polyurethanes derived from hydrolysable aminesand isocyanates of formula G and H respectively. These polymers are willhave tunable mechanical and hydrolytic degradation properties and areexpected to hydrolyze back to safe and biocompatible molecules includingglycolic acid, lactic acid etc and parent amino acid.

In yet another embodiment the present invention introduces multiarmedhydrolysable aromatic amines of formula I prepared by reactingfunctionalized nitrophenylalanine i.e. nitrophenylalanine functionalizedwith safe and biocompatible molecules (e.g. glycolic acid, lactic acid,caprolactone, and dioxanone) with amino benzoic acid and amino phenol.

Wherein:

-   Each X is independently selected from the X Options;-   And wherein p is independently selected from 0 to 6 inclusive; and-   Each Y is independently selected from the Y Options.

Structures of representative examples of absorbable amines of theformula (I) including but not limited to the following:

The present invention also introduces multiarmed hydrolysable aromaticisocyanates of formula J derived from hydrolysable amines of generalformula I:

Wherein:

-   Each X is independently selected from the X Options;-   And wherein p is independently selected from 0 to 6 inclusive; and,-   Each Y is independently selected from the Y Options.

Structures of representative examples of absorbable isocyanates of theformula (J) including but not limited to the following:

In another embodiment the present invention also introduces a drug andamino acid releasing monomers or macromers represented by generalformula K prepared by reacting functionalized amino acids i.e. aminoacids functionalized with safe and biocompatible molecules (e.g.glycolic acid, lactic acid, caprolactone, and dioxanone) with drugmolecules. These monomers and macromers are expected to release safe andbiocompatible molecules along with parent amino acids and drug moleculesupon hydrolysis. These monomers and macromers are expected to be apotential candidates for site specific delivery of drugs andbiologically active agents:

Where in

-   Each Y′ is independently selected from the Y′ Options;-   —OCOCH₂— (glycolic moiety)-   —OCOCH(CH₃)— (lactic moiety)-   —OCOCH₂OCH₂CH₂— (dioxanone moiety)-   —OCOCH₂CH₂CH₂CH₂CH₂— (caprolactone moiety)-   —OCO(CH₂)_(y)— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —OCO(CH₂CH₂O)_(m)CH₂—; where m is integer between 2-24 inclusive;    and,-   And wherein p is independently selected from 0 to 6 inclusive; and,-   And Q′ is the residue of a diol;-   Drug=any biologically active substance containing one or more —OH,    —COOH or —NH₂ functional groups by which it is covalently bound to a    Y; and-   R is a residue of an amino acid.

Drug releasing amino acid monomers or macromers of formula K includingbut not limited to the following:

Naproxen, paracetamol, acetaminophen and acetylsalicylic acid areexamples of biologically active phenolics that belong to the class ofdrugs called non-steroidal anti -inflammatory drugs or NSAIDs. TheNSAIDs provide relief by blocking the action of prostaglandins, whichare hormone-like substances that contribute to pain, inflammation, feverand muscle cramps.

Examples of biologically active carboxylic acid compounds of thisinvention include but not limites to Acemetacin, Aceclofenac,Acediasulfone, Adipiodone, Alminoprofen, Amlexanox, Anileridine,Baccofen, Balsalazide sodium, Bentiromide, Benzocaine, Bumetanide,Carprofen, Carzenide, Cinmetacin, Clometacin, Cromoglicic acid,Diclofenac, Diflunisal, Eprosartan, Fendosal, Flufenamic acid,Furosemide, Indometacin, Iobenzamic acid, Iocarmic acid, Iocetamic acid,Iodoxamic acid, Ioglycamic acid, Iophenoic acid, Iotroxic acid,Mefenamic acid, Naproxen, Nedocromil, Repaglinide, Salazosulfapyridine,Salicylic Acid, Salsalate, and Sarpogrelate.

The present invention also provides a drug, amino acid and nitric oxidereleasing monomers and macromers represented by general formula Lprepared by reacting functionalized amino acids i.e. amino acidsfunctionalized with safe and biocompatible molecules (e.g. glycolicacid, lactic acid, caprolactone, and dioxanone) with drug moleculesfunctionalized with nitric oxide moieties. These monomers and macromersare expected to release safe and biocompatible molecules along withparent amino acids and drug molecules along with nitric oxide uponhydrolysis. These monomers and macromers are expected to be a potentialcandidates for site specific delivery of drugs, nitric oxide andbiologically active agents:

Where in

-   Each X′ is independently selected from the X′ Options;-   p is independently selected from 0 to 6 inclusive;-   Q′ is the residue of diol;-   Drug=any biologically active substance containing two or more —OH,    —COOH or —NH₂ functional groups by which it is covalently bound to a    X′; and-   R is a residue of an amino acid.

Drug and Nitric Oxide releasing amino acid monomers of formula Lincluding but not limited to the following:

The present invention also introduces hydrolysable amide diacids offormula M derived from amino acids and symmetrical and unsymmetricalether acids for the preparation of absorbable polyester amides:

Wherein:

-   Q, with the adjacent carbonyl groups, is residue of symmetrical    and/or unsymmetrical ether acids; and-   R is a residue of an amino acid.

Representative examples of absorbable amide diacids of the formula Mincluding but not limited to the following:

Exemplary compounds that can be the symmetrical and/or unsymmetricalether acids include:

Q contains a primary (long) chain of 2 up to 200 chain atoms (notincluding H) that are predominantly —CH₂—, where in the primary chain—CH₂— groups may be substituted with —O—, or —S—. Alkyl and aryl can besubstituted with lower alkyl group(s) of C1 to C6. In certainembodiments, the alkyl of R′ is of long chain of 2 to 24 atoms, or from2 to 6 atoms.

In another embodiment the present invention also introduces aromaticisocyanates of formula N derived from nitrophenylalanine. These aromaticisocyanates can be used to prepare absorbable polyurethanes and the likecontaining long chain hydrophobic or hydrophilic pendant chains:

WhereinR″ is alkyl, aryl or arylalkyl, or R″ is a biologically activesubstance.

Representative examples of diisocyanates of formula N including but notlimited to the following are shown below:

The present invention also introduces absorbable or nonabsorbable andbiocompatible polyurethanes and the like prepared from isocyanates offormula N.

In another embodiment the present invention also introduces aromaticisocyanates derived from 3-nitrotyrosine. These aromatic isocyanates canbe used to prepare absorbable polyurethanes and the like containing longchain hydrophobic or hydrophilic pendant chains:

The present invention also introduces absorbable polyurethanes and thelike prepared from isocyanates derived from 3-nitrotyrosin

Absorbable amines derived from 3-Nitrotyrosine of the formula P:

Wherein:

-   Each Y is independently selected from the Y Options;-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   R″ is alkyl, aryl or arylalkyl, or R″ is a biologically active    substance.

Structures of representative examples of absorbable amines of theformula (P) includes the following:

Absorbable isocyanates derived from 3-Nitrotyrosine of the formula (S)

Wherein:

-   Each Y is independently selected from the Y Options;-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   R″ is alkyl, aryl or arylalkyl, or R″ is a biologically active    substance.

Structures of representative examples of absorbable isocyanates of theformula (S) includes the following

Absorbable amines derived from 3-Nitrotyrosine of the formula (T):

Wherein:

-   Each X is independently selected from the X Options;-   p is indepentyl selected from 0 to 6 inclusive;-   Y is independently selected from the Y Options; and-   R″ is alkyl or aryl, arylalkyl, or R″ is a biologically active    substance.

Structures of representative examples of absorbable amines of theformula (T) includes the following

Absorbable isocyanates derived from 3-Nitrotyrosine of the formula (U):

Wherein:

-   Each X is independently selected from the X Options;-   p is indepentyl selected from 0 to 6 inclusive; and,-   Y is independently selected from the Y Options;-   R″ is alkyl or aryl, arylalkyl, or R″ is a biologically active    substance.

Structures of representative examples of absorbable isocyanates of theformula (U) include the following

Yet another aspect of the present invention is to prepare absorbablepolyurethanes and the like from at least one isocyanate derived from3-Nitrotyrosine of the formula V:

WhereinR″ is alkyl, aryl or arylalkyl, or R″ is a biologically activesubstance.

Diisocyanate the formula (V) including but not limited to the following:

In another embodiment the present invention also introduces amidediacids of the formula W derived from diamines and symmetrical andunsymmetrical ether acid:

Where in Q is a residue of symmetrical and/or unsymmetrical ether acids;andRx is the residue of a diamine where in Rx is (a) alkyl, aryl orarylalkyl, or the residue (including the vicinal amines shown above) ofa diamino amino acid or amino acid analog, such as L-lysine andaminophenyl alanine.

Amide diacids of the formula (W) including but not limited to thefollowing:

The present invention also introduces absorbable polyester amidesprepared from amide diacids of formula W.

Another embodiment of the invention provides an amine or isocyanatederived from nitrophenylalanine of the formula Z or ZZ:

Wherein:

-   Each Y is independently selected from:-   —COCH₂O— (glycolic moiety)-   —COCH(CH₃)O— (lactic moiety)-   —COCH₂OCH₂CH₂O— (dioxanone moiety)-   —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone moiety)-   —CO(CH₂)_(y)O— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —CO(CH₂CH₂O)_(m)CH₂O—; where m is integer between 2-24 inclusive;-   p is independently selected from 0 to 6 inclusive;-   Each X is independently:-   —OCH₂CO— (glycolic ester moiety)-   —OCH(CH₃)CO— (lactic ester moiety)-   —OCH₂CH₂OCH₂CO— (dioxanone ester moiety)-   —OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone ester moiety)-   —(CH₂)_(y)COO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —(CH2CH2O)_(m)CH2COO—; where m is integer between 2-24 inclusive;    and-   R′ is a residue of a diol where in R′ is alkyl, aryl or arylalkyl.

Structures of representative examples of amines of the formula (Z)include the following:

Structures of representative examples of isocyanates of the formula (ZZ)include the following

In other embodiments, absorbable polyurethanes and the like of thepresent invention, such as in connection with their use as stents, stentcoatings, films, adhesion prevention barrier, scaffolds and polyurethanefoams, highly porous foams, and reticulated foams may be derived fromisocyanates described and claimed in U.S. Patent Application PublicationNos. 20060188547, 20090292029, European Patent Publication No. EP1937182 and WO 2007030464 and reacting them with chain extenders andpolyuols.

In certain embodiments, the present invention provides absorbablepolyurethanes and the like derived from isocyanatres that are derivedfrom amino acids selected from tyrosine, 3-aminotyrosine,3-chlorotyrosine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, homotyrosine,3-iodotyrosine, 3-nitrotyrosine, 2-tyrosine, 3-tyrosine,4-hydroxy-3-nitrophenylalanine, 5-hydroxytryptophan,3-nitro-4-hydroxyphenylalanine, thyronine, 3,4-dihydroxyphenylalanine,4-hydroxyphenylglycine, 3-aminosalicylic acid; 4-aminosalicylic acid;and 5-aminosalicylic acid. The amino acids used in the present inventioninclude all of the possible stereoisomers (e.g., D, L, D/L), unless aspecific isomer is identified.

In another embodiment, absorbable polyurethanes and the like of thepresent invention may be derived from safe and biocompatible aminoacids. Polyurethanes and the like resulting from these isocyanates areexpected to be safe and biocompatible. Although all the naturallyoccurring and synthetic amino acids can be used as precursors forpreparation of hydrolysable isocyanates in the present invention,however, examples of amino acid including but not limited to alanine,asparagine, aspartic acid, gamma amino butyric acid, glycine, glutamicacid, valine, lysine, isoleucine, leucine, tyrosine, ornithine,phenylalanine and sarcosine, 3-aminotyrosine, 3-chlorotyrosine,3,5-dibromotyrosine, 3,5-diiodotyrosine, homotyrosine, 3-iodotyrosine,3-nitrotyrosine, 2-tyrosine, 3-tyrosine, 4-hydroxy-3-nitrophenylalanine,5-hydroxytryptophan, 3-nitro-4-hydroxyphenylalanine, thyronine,3,4-dihydroxyphenylalanine, 4-hydroxyphenylglycine, 3-aminosalicylicacid; 4-aminosalicylic acid; and 5-aminosalicylic acid.

In another embodiment, branched or linear absorbable polyurethanes andthe like of the present invention may also be derived from isocyanatesbased on cycloaliphatic amino acids such as aminocyclohexanecarboxylicacid as well as cycloaliphatic amino alcohols such as aminocyclohexanol.Polyurethanes and the like from these isocyanates can be preparedaccording to the procedures described in U.S. Patent ApplicationPublication Nos. 20060188547, 20090292029, European Patent PublicationNo. EP 1937182 and WO 2007030464. Polyurethanes and the like resultingfrom cycloaliphatic amino acids as well as cycloaliphatic amino alcoholswill find use in a variety of applications including biomedicalapplications wherein controlled hydrolytic degradation is desired.

In another embodiment absorbable polyester amides can be prepared byreaction of amide diols, and/or absorbable polyols, with diacidsincluding but not limited to oxalic acid, succinic acid, malonic acid,butanedioic acid, adipic acid, azelaic acid, sebacic acid, diglycolicacid, 3,6-dioxaoctanedioic acid, 3,6,9-trioxaundecanoic acid,functionalized oxaacids, polyethyleneglycol diacids of average molecularweight from 300 to 2000 and blends thereof.

In another embodiment absorbable polyamides will be prepared by reactionof diamines with diacids including but not limited to oxalic acid,succinic acid, malonic acid, butanedioic acid, adipic acid, azelaicacid, sebacic acid, diglycolic acid, 3,6-dioxaoctanedioic acid,3,6,9-trioxaundecanoic acid, functionalized oxaacids, polyethyleneglycoldiacids of average molecular weight from 300 to 2000 and blends thereof.

In another embodiment of the present invention, absorbablepolyurethanes, polyamides, and polyesteramides of the present inventioncan be further polymerized with lactone monomers including but notlimited to glycolide, lactide, caprolactone, p-dioxanone, TMC,δ-valerolactone, β-butyrolactone, morpholinedione, pivalolactone,ε-decalactone, 2,5-diketomorpholine and combinations thereof in order tocontrol physical and biological properties.

The present invention introduces novel functionalized amino acids basedhydrolysable monomers, macromers and absorbable polymers derived fromthem. The novel functionalized amino acid based monomers, macromers ofthe present invention are expected to have controllable hydrolysisprofiles, improved bioavailability, improved efficacy, and enhancedfunctionality. Some of the functionalized amino acids can be monomersfrom which polymers can be made that are useful for medicalapplications. For example, functional monomers of the present inventioncan be polymerized to form absorbable polymers (e.g., polyesters,polyamides, polyester amides, polyurethanes, and polyanhydrides). It canbe advantageous for the monomers that are to be polymerized to have atleast two active sites (e.g., 2 or 3) for polymerization. These activesites include amino, isocyanate and carboxylic acid groups. Thefunctionalized amino acids with at least two active sites can also becopolymerized with selected difunctional molecules (e.g., dicarboxylicacids, dialcohols, diisocyanates, amino-alcohols, hydroxy-carboxylicacids, and diamines) based on the starting functionalized amino acid toform absorbable polymers. The polymers (and copolymers) of the presentinvention can also be further reacted/polymerized to form additionaluseful polymers of the present invention.

As described herein, the functionalized monomers, macromers and polymersof the present invention are useful in medical applications/medicaldevices. Medical application/medical devices, as used herein, encompassmedical and biomedical applications and include all types ofapplications involved in the practice of medicine that would benefitfrom a material that decomposes harmlessly within a known period oftime. Examples include medical and surgical devices, which include drugdelivery systems (e.g., a site-specific or systemic drug deliverysystems or matrices), tissue engineering (e.g., tissue scaffold), stentcoatings, stents, porous devices, implantable medical devices, moldedarticles (e.g., vascular grafts, stents, bone plates, sutures,implantable sensors, and barriers for surgical adhesion prevention),wound closure devices (e.g., surgical clips, staples, and sutures),coatings (e.g., for endoscopic instruments, sutures, stents, andneedles), fibers or filaments (which may be attached to surgical needlesor fabricated into materials including sutures or ligatures,multifilament yarn, sponges, gauze, tubes, and sheets for typing up andsupporting damaged surface abrasions), rods, films (e.g., adhesionprevention barriers), knitted products, foodstuffs, nutritionalsupplements, nutriceuticals, cosmetics, pharmaceuticals, biodegradablechewing gums, flavors, enhanced drugs, drug intermediates, cancerpreventing agents, antioxidants, controlled release preparations, andsolvents for drugs. Examples of knitted products, woven or non-woven,and molded products include: burn dressings; hernia patches; medicateddressings; fascial substitutes; gauze, fabric, sheet, felt, or spongefor liver hemostasis; gauze bandages; arterial graft or substitutes;bandages for skin surfaces; suture knot clip; orthopedic pins, clamps,screws, and plates; clips (e.g., for vena cava); staples; hooks,buttons, and snaps; bone substitutes (e.g., mandible prosthesis);intrauterine devices (e.g., spermicidal devices); draining or testingtubes or capillaries; surgical instruments; vascular implants orsupports; vertebral discs; extracorporeal tubing for kidney andheart-lung machines; and, artificial skin.

It would be readily apparent to one of ordinary skill in the art oncearmed with the teachings in the present application that the isocyanatesof the present invention may be reacted with a variety of reactants thatare typically employed in the preparation of bioabsorbable andbiocompatible polyurethanes and/or polyester urethanes, preferably withtunable physical, mechanical properties and/or hydrolytic degradationprofiles. It would also be apparent to the ordinarily skilled artisanthat the terminal groups for given polyurethane, or polyester may bederivatized by further reacting the polyurethane and/or polyesters withadditional derivatizing agents. Polyurethanes terminated with —NCO orhydroxyl groups can be prepared by varying the ratio of isocyanates:hydroxyl groups in the reaction mixture i.e. (isocyanates, chainextender and polyol). Polyurethanes with high molecular weights areformed when the ratio of isocyanates: hydroxyl group is 1. Furthermore,by varying the ratio of isocyanates: hydroxyl groups in the reactionmixture, polyurethanes with tunable physical and mechanical propertiescan be obtained. It would also be apparent to the ordinarily skilledartisan that the terminal groups for given polyurethane, or polyestermay be derivatized by further reacting the polyurethane and/orpolyesters with additional derivatizing agents.

In one form, the absorbable polyurethanes and polyester amides describedherein are biodegradable and in certain aspects biocompatible andsuitable for use in medicine. Such polyurethanes, and/or polyesterscombine the good mechanical properties of polyurethanes with thedegradability of polyesters.

The absorbable polyurethane and/or polyester amides herein is suitablefor use in a wide variety of applications. Since the degradationproducts of the biocompatible polyurethanes and/or polyesters describedherein are non-toxic, they are advantageously suitable for biomedicaluses. For example, the properties of the polymer may be tunable, i.e.,they may be made to degrade more slowly or more quickly by reducing orincreasing respectively the number of ester linkages in the polymericchain, and can thus be utilized for fabricating short-term or long-termimplantable surgical materials.

The polyurethanes and/or polyester amides, polyureas, polyepoxides maybe formed into articles and formulations using any known technique, suchas, for example, extrusion, molding and/or solvent casting, blending.The polyurethanes and/or polyesters, polyureas, polyepoxides may be usedalone, blended with other absorbable compositions, or in combinationwith non-bioabsorbable components. A wide variety of articles orformulations may be manufactured from the polyurethanes and/orpolyesters described herein. These include but are not limited to clipsand other fasteners, staples, sutures, pins, screws, prosthetic devices,wound dressings or coverings, burn dressings or coverings, drug deliverydevices, anastomosis rings, stents, stent coatings, films, scaffolds,polyurethane foams, bone wax formulations and other implantable medicaldevices. Examples of medical implantable devices include prostheticdevices, stents, sutures, staples, clips and other fasteners, screws,pins, films, meshes, drug delivery devices or systems, anastomosisrings, surgical dressings and the like. In some embodiments, thesurgical articles or components thereof include stents, stent coatings,adhesion prevention barrier, wound coverings, burn coverings, foams,tissue engineering scaffolds, films, implantable medical devices, and/orcontrolled drug delivery systems, more preferably stents, stentcoatings, wound and/or burn coverings, bone wax formulations and/orcontrolled delivery systems. In certain other embodiments, the surgicalarticles or components thereof include sutures, ligatures, needle andsuture combinations, surgical clips, surgical staples, surgicalprosthetic devices, textile structures, couplings, tubes, supports,screws, or pins. In certain drug delivery systems, the systems comprisea polyurethane, and/or polyester in admixture with a biologically orpharmaceutically active agent. Non-limiting examples of polymericcarriers in such drug delivery systems and/or pharmaceuticalcompositions include self-supporting films, hollow tubes, beads, and/orgels. Other uses of the surgical article include their use as a scaffoldfor tissue engineering comprising a porous structure for the attachmentand proliferation of cells, such as in vitro or in vivo. Thepolyurethanes and/or polyesters herein may also be used to fabricatedegradable containers and packaging materials which can degrade inlandfills in contrast to existing non-degradable materials which presentenvironmental concerns.

The polymers of the present invention may be used as pharmaceuticalcarriers in a drug delivery matrix, i.e., a matrix for a biologicallyactive substance (i.e., agent). The matrix may be formed by mixing thepolymer with a biologically active agent. The biologically active agentcan be dispersed into the polymer solution for example duringpreparation of matrix or via melt blending. A vast variety of differentbiologically active agents may be used in conjunction with the polymersof the invention. In general, therapeutic agents administered via thepharmaceutical compositions of the invention include, withoutlimitation: anti-infectives such as antibiotics and antiviral agents;analgesics and analgesic combinations; anorexics; anti-helmintics;anti-arthritics; anti-asthmatic agents; anticonvulsants;antidepressants; anti-diuretic agents; anti-diarrheals; anti-histamines;anti-inflammatory agents; anti-migraine preparations; anti-nauseants;anti-neoplastics; anti-parkinsonism drugs; anti-pruritics;anti-psychotics; anti-pyretics, anti-spasmodics; anti-cholinergics;sympathomimetics; xanthine derivatives; cardiovascular preparationsincluding calcium channel blockers and beta-blockers such as pindololand anti-arrhythmics; anti-hypertensives; diuretics; vasodilatorsincluding general coronary, peripheral and cerebral; central nervoussystem stimulants; cough and cold preparations, including decongestants;hormones such as estradiol and other steroids, includingcorticosteroids; hypnotics; immunosuppressives; muscle relaxants;para-sympatyholytics; psychostimulants; sedatives; and tranquilizers;and naturally derived or genetically engineered proteins,polysaccharides, glycoproteins or lipoproteins.

The drug delivery matrix may be administered in any suitable dosage formsuch as oral, parenteral, subcutaneously as an implant, vaginally or asa suppository. Matrix formulations containing polymers of the inventionmay be formulated by mixing one or more therapeutic agents with thepolymer. The biologically active agent may be present as a liquid, afinely divided solid, or any other appropriate physical form. Typically,the matrix will include one or more additives, e.g., nontoxic auxiliarysubstances such as diluents, carriers, excipients, stabilizers or thelike. However, the presence of such additives is optional. Othersuitable additives may be formulated with the polymers of this inventionand pharmaceutically active agent or compound. If water is to be used asan additive, it is preferably be added immediately beforeadministration.

The amount of biologically active agent will be dependent upon theparticular agent employed and medical condition being treated.Typically, the amount of drug represents about 0.001% to about 70%, moretypically about 0.01% to about 50%, and most typically about 0.1% toabout 20% by weight of the matrix.

The quantity and type of polymer incorporated into a parenteral dosageform will vary depending on release profile desired and the amount ofdrug employed. The product may contain blends of polymers of thisinvention to provide the desired release profile or consistency to agiven formulation.

The polymers of this invention, upon contact with body fluids includingblood or the like, undergo gradual degradation (mainly throughhydrolysis) with concomitant release of the dispersed drug for asustained or extended period (as compared to the release from anisotonic saline solution). This may result in prolonged delivery (overabout one to about 2,000 hours, preferably about two to about 800 hours)of effective amounts (including, for example, about 0.0001 mg/kg/hour toabout 10 mg/kg/hour) of the drug. This dosage form may be administeredas necessary depending on the subject being treated, the severity of theaffliction, the judgment of the prescribing physician, and the like.

Individual formulations of drugs and polymers of this invention may betested in appropriate in vitro and in vivo models to achieve the desireddrug release profiles. For example, a drug may be formulated with apolymer of this invention and administered to an animal (e.g., orally).The drug release profile may be monitored by appropriate means, such asby taking blood samples at specific times and assaying the samples fordrug concentration. Following this or similar procedures, those skilledin the art may formulate a variety of formulations.

The absorbable polymer material of the present invention are believed tobe useful for use as a tissue engineering scaffold, i.e., as a structurefor the growth or regeneration of tissue. Polyurethanes may lendthemselves to such uses since the enzyme-catalyzed degradation may insome cases work concurrently with the migration or growth of cells intothe material, while desirably degrading in the process into itssubstantially non-toxic constituents. It is also possible, in somecases, that cells migrating into or located adjacent the matrix maythemselves exude proteolytic enzymes that will also mediate hydrolyticcleavage.

Such tissue engineering scaffolds may have applications in theregeneration of skin and other organs, bone, cartilage, ligaments,tendons, bladder and other tissue. The polyurethane material may also beuseful in the production of sutures, which require good mechanicalstrength, and drug release matrices, in view of their need for non-toxicdegradability. The polyurethane material may also be useful for othernon-biomedical applications, where degradability into substantiallynon-toxic constituents is an asset. The polyurethane material lendsitself to sterilization by such techniques as gamma radiation andethylene oxide treatments.

Fibers made from the present polyurethanes and/or polyester amides canbe knitted or woven with other fibers, either absorbable ornon-absorbable to form meshes or fabrics. Compositions including thesepolyurethanes and/or polyesters may also be used as absorbable coatingfor surgical devices.

In another aspect, the compositions containing the polyurethanes and/orpolyester amides described herein may be used to make reinforcedcomposites. Thus, for example, the polyurethane and/or polyestercomposition may form the matrix of the composite and may be reinforcedwith bioabsorbable or non-bioabsorbable fibers or particles.Alternatively, a matrix of any absorbable or non-bioabsorbable polymercomposition may be reinforced with fibers or particulate material madefrom compositions containing the polyurethanes and/or polyestersdescribed herein.

In an alternative embodiment, the branched absorbable polyurethanes,and/or polyesters described herein may be admixed with a filler. Thefiller may be in a particulate form, such as granulates and staplefibers. While any known filler may be used, hydroxyapatite, tricalciumphosphate, bioglass or other bioceramics are the exemplary fillers. Forexample, from about 10 grams to about 400 grams of filler are mixed withabout 100 grams of polymer. The filled, cross-linked polymers areuseful, for example, as a molding composition.

It is further contemplated that one or more medico-surgically usefulsubstances (biologically active agents) may be incorporated intocompositions containing the absorbable polyurethanes and/or polyesteramides described herein. Examples of such biologically active agentsinclude, for example, those which accelerate or beneficially modify thehealing process when particles are applied to a surgical repair site.For example, articles made from compositions containing the presentpolyurethanes and/or polyesters may carry a therapeutic agent which willbe deposited at the repair site. The biologically active agent may bechosen for its antimicrobial properties, capability for promoting repairor reconstruction and/or new tissue growth. Antimicrobial agents such asbroad spectrum antibiotic, for example, gentamycin sulfate,erythromycin, or derivatized glycopeptides which are slowly releasedinto the tissue may be applied in this manner to aid in combatingclinical and sub-clinical infections in a tissue repair site. To promoterepair and/or tissue growth, one or several growth promoting factors maybe introduced into the articles, e.g., fibroblast growth factor, bonegrowth factor, epidermal growth factor, platelet derived growth factor,macrophage derived growth factor, alveolar derived growth factor,monocyte derived growth factor, magainin, and the like. Some therapeuticindications are: glycerol with tissue or kidney plasminogen activator tocause thrombosis, superoxide dismutase to scavenge tissue damaging freeradicals, tumor necrosis factor for cancer therapy or colony stimulatingfactor and interferon, interleukin-2 or other lymphokine to enhance theimmune system.

It is contemplated that it may be desirable to dye articles made fromcompositions containing the present branched absorbable polyurethanesand/or polyesters in order to increase visibility of the article in thesurgical field. Dyes, such as those known to be suitable forincorporation in sutures, may be used. Such dyes include but are notlimited to carbon black, bone black, D&C Green No. 6, and D&C Violet No.2 as described in the handbook of U.S. Colorants for Food, Drugs andCosmetics by Daniel M. Marrion (1979), the disclosures of which arehereby incorporated herein by reference, in their entireties.Preferably, articles in accordance with this disclosure may be dyed byadding up to about a few percent and preferably about 0.2% dye to theresin composition prior to extrusion.

Biologically active hydroxy compounds that can be used as a pendantgroup or covalently bonded to the amino acid of present inventioninclude acenocoumarol, acetarsol, actinoquinol, adrenalone, alibendol,amodiaquine, anethole, balsalazide, bamethan, benserazide, bentiromide,benzarone, benzquinamide, bevantolol, bifluranol, buclosamide,bupheniode, chlorotrianisene, chloroxylenol, cianidanol, cinepazide,cinitapride, cinepazide, cinmetacin, clebopride, clemastine, clioquinol,cyclovalone, cynarine, denopamine, dextroythyroxine, diacerein,dichlorophen, dienestrol, diethylstilbestrol, diflunisal,diiodohydroxyquinoline, dilazep, dilevalol, dimestrol, dimoxyline,diosmin, dithranol, dobutamine, donepezil, dopamine, dopexamine,doxazosin, entacapone, epanolol, epimestrol, epinephrine, estradiolvalerate, estriol, estriol succinate, estrone, etamivan, etamsylate,ethaverine, ethoxzolamide, ethyl biscoumacetate, etilefrine, etiroxate,exalamide, exifone, fendosal, fenoldopam mesilate, fenoterol, fenoxedil,fenticlor, flopropione, floredil, fluorescein, folescutol, formoterol,gallopamil, gentistic acid, glaziovine, glibenclamide, glucametacin,guajacol, halquinol, hexachlorophene, hexestrol, hexobendine,hexoprenaline, hexylresorcinol, hydroxyethyl salicylate,hydroxystilbamidine isethionate, hymecromone, ifenprodil, indomethacin,ipriflavone, isoetarine, isoprenaline, isoxsuprine, itopridehydrochloride, ketobemidone, khellin, labetalol, lactylphenetidin,levodopa. levomepromazine, levorphanol, levothyroxine, mebeverine,medrylamine, mefexamide, mepacrine, mesalazine, mestranol, metaraminol,methocarbamol, methoxamine, methoxsalen, methyldopa, midodrine,mitoxantrone, morclofone, nabumetone, naproxen, nitroxoline,norfenefrine, normolaxol, octopamine, omeprazole, orciprenaline,oxilofrine, oxitriptan, oxyfedrine, oxypertine, oxyphenbutazone,oxyphenisatin acetate, oxyquinoline, papaverine, paracetanol,parethoxycaine, phenacaine, phenacetin, phenazocine, phenolphthalein,phenprocoumon, phentolamine, phloedrine, picotamide, pimobendan,prenalterol, primaquine, progabide, propanidid, protokylol,proxymetacaine, raloxifene hydrochloride, repaglinide, reproterol,rimiterol, ritodrine, salacetamide, salazosulfapyridine, salbutamol,salicylamide, salicylic acid, salmeterol, salsalate, sildenafil,silibinin, sulmetozin, tamsulosin, terazosin, terbutaline, tetroxoprim,theodrenaline, tioclomarol, tioxolone, alpha-tocopherol (vitamin E),tofisopam, tolcapone, tolterodine, tranilast, tretoquinol, triclosan,trimazosin, trimetazidine, trimethobenzamide, trimethoprim, trimetozine,trimetrexate glucuronate, troxipide, verapamil, vesnarinone,vetrabutine, viloxazine, warfarin, xamoterol.

Other biologically active phenolics that can be used include acacetin,4-acetamido-2-methyl-1-naphthol, acetaminophen, albuterol, allenolicacid, aloe emodin, aloin, β-amino-4-hydroxy-3,5-di-iodohydrocinnamicacid, N-(5-amino-2-hydroxyphenyl) -benzeneacetamide, 4-amino-1-naphthol,3-aminosalicylic acid, 4-aminosalicylic acid, anacardic acid, p-anol,anthragallol, anthralin, anthranol, anthrarobin, anthrarobin, apigenin,apiin, apocynin, aspidinol, aspirin, baptigenin, benzestrol,benzoresorcinol, bisphenol a, bisphenol b, butylated hydroxylanisole,butylated hydroxytoluene, capobenic acid,trans-1-(3′-carboxy-4′-hydroxyphenyl)-2-(2″,5″-dihydroxyphenyl)ethane,catechin, chlorogenic acid, m -chlorophenol, 5-chloro-8-quinolinol,chloroxylenol, chlorquinaldol, chromo-nar, chrysin, cinametic acid,clorophene, coniferyl alcohol, p-coumaric acid, coumes-trol, coumetarol,daphnetin, datiscetin, deoxyepinephrine, 3,5-diiodothyronine,3,5-di-iodotyrosine, dimethophrine, diosmetin, diresorcinol, disoprofol,dopa, dopamine, drosophilin a, efloxate, ellagic acid, embelin, Equol,eriodictyol, esculetin, esculin, ethylnorepinephrine, ethyl vanillin,eugenol, eupatorin, fenadiazole, ferulic acid, fisetin,3-fluoro-4-hydroxyphenylacetic acid, fraxetin, fustin, galangin,gallacetophe-none, gallic acid, gardenins, genistein, gentisyl alcohol,gepefrine, geranylhydroqui-none, [6]-gingerol, gossypol, guaiacol,guaifenesin, harmalol, hematoxylin, hinderin, homoeriodictyol,homogentisic acid, homovanillic acid, hydroxyamphetamine,2-hyd-roxy-5-(2,5-dihydroxybenzylamino)-2-hydroxybenzoic acid,4-hydroxy-3-methoxy-mandelic acid, n-(p-hydroxyphenyl)glycine,hydroxyprocaine, 8-hydroxyquinoline, hypericin, irigenin, isoproterenol,isoquercitrin, isothebaine, kaempferol, liothyronine, luteolin,mangostin, 5,5′-methylenedisalicylic acid, n-methylepinephrine,metyrosine, morin, mycophenolic acid, myricetin, naringenin, nylidrin,orcinol, osalmid, osthole, oxantel, paroxypropione, pentachlorophenol,3-pentadecylcatechol, p-pentyloxy -phenol, phloretin, phloroglucinol,pinosylvine, plumbagin, pyrocatechol, pyrogallol, quercetagetin,quercetin, resacetophenone, rhamnetin, rhein, sakuranetin, salicylalcohol, salicylanilide, 4-salicyloylmorpholine, salsalate, scopoletin,scutellarein, serotonin,(3,4,5-trihydroxyphenyl)methylenepropanedinitrile, thymol, thyropropicacid, thyroxine, tiratricol, tyrosine, vanillic acid, and vanillin.

Further biologically active carboxylic acid and/or amine compounds thatcan be used as a pendant group or covalently bonded to the amino acid ofthe present invention include Acemetacin, Aceclofenac, Acediasulfone,Adipiodone, Alminoprofen, Amisulpride, Amlexanox, Amodiaquine,Amosulalol, Amoxicillin, Amsacrine, Anileridine, Azacyclonol, Baccofen,Balsalazide sodium, Bentiromide, Benzocaine, Bromopride, Bumetanide,Carprofen, Carvedilol, Carzenide, Cefprozil, Cinitapride, Cinmetacin,Clebopride, Clenbuterol, Clometacin, Cromoglicic acid, Diclofenac,Diflunisal, Eprosartan, Ethoxzolamide, Fendosal, Flufenamic acid,Furosemide, Ibuprofen, Indometacin, Iobenzamic acid, Iocarmic acid,Iocetamic acid, Iodoxamic acid, Ioglycamic acid, Iophenoic acid,Iotroxic acid, Mefenamic acid, Nadoxolol, Naproxen, Nedocromil,D-Norpseudoephedrine, paracetamol Repaglinide, Salazosulfapyridine,Salicylic Acid, Salsalate and Sarpogrelate.

Examples of biologically active dihydroxy compounds that can be used toas a pendant group or covalently bonded to the amino acid of presentinvention of present invention include Adrenalone, Alfuzosin, Alibendol,Amrubicin, Apomorphine, Bamethan, Benzquinamide, Bevantolol, Bifluranol,Bisacodyl, Brodimoprim, Bunazosin, Bupheniode, Carbidopa, Carbuterol,Cyclofenil, Cyclovalone, Daunorubicin, Dichlorophen, Dienestrol,Diethylstilbestrol, Dimestrol, Dithranol, Donepezil, Doxefazepam,Doxorubicin, Entacapone, Epinepheine, Epirubicin, Esomeprazole,Etamivan, Etamsylate, Etilefrine, Ezetimibe, Fenticlor, Fluorescein,Folescutol, Formoterol, Gefitinib, Hexestrol, Hexylresorcinol,Hydroxyethyl salicylate, Ifenprodil, Isoetarine, Isoxsuprine, Itopride.HCl, Khellin, Labetalol, Mitoxantrone, Morclofone, Moxaverine,Normolaxol, Omeprazole, Oxilofrine, Oxepertine, Phenacaine,Phenolphthalein, Prazosin, Tolcapone, Vesnarinone, and Vetradutine.

Examples of biologically active diamino compounds that can be used as apendant group or covalently bonded to the amino acid of presentinvention of present invention include Amisulpride, Amodiaquine,Amosul-alol, Amoxicillin, Amsacrine, Azacyclonol, Bromopride,Carvedilol, Cefprozil, Cinitapride, Clebopride, Clenbuterol,Ethoxzolamide, Nadoxolol, and D-Norpseudoephedrine.

Examples of biologically active hydroxy/amino compounds that can be usedas a pendant group include Amisulpride, Amodiaquine, Amosulalol,Amoxicillin, Amsacrine, Azacyclonol, Bromopride, Carvedilol, Cefprozil,Cinitapride, Clebopride, Clenbuterol, Ethoxzolamide, Nadoxolol,D-Norpseudo-ephedrine, and paracetamol.

Examples of biologically active dicarboxylic acid compounds that can beused as a pendant group or covalently bonded to the amino acid ofpresent invention of present invention include Adipiodone, Cromoglicicacid, Eprosartan, Iocarmic acid, Iodoxamic acid, Ioglycamic acid,Iotroxic acid, Nedocromil.

Examples of biologically active hydroxy/carboxylic acid compounds thatcan be used as a pendant group or covalently bonded to the amino acid ofpresent invention include Acemetacin, Bentiromide, Cinmetacin,Clometacin, Diflunisal, Fendosal, Indometacin, Iophenoic acid, Naproxen,Repaglinide, Salazosulfapyridine, Salicylic Acid, Salsalate, andSarpogrelate.

Examples of biologically active hydroxyl-acids for use as the pendantgroup or covalently bonded to the amino acid of present inventioninclude 4-hydroxycinnamic acid, caffeic acid, chlorogenic acid, ferulicacid, sinapic acid, vanillic acid, Acemetacin, Bentiromide, Cinmetacin,Clometacin, Diflunisal, Fendosal, Indometacin, Iophenoic acid, Naproxen,Repaglinide, Salazosulfapyridine, Salicylic Acid, Salsalate, andSarpogrelate.

Examples of useful biologically active amino/carboxylic acid compoundsthat can be used as a pendant group of present invention includeAceclofenac, Acediasulfone, Alminoprofen, Amlexanox, Anileridine,Baccofen, Balsalazide sodium, Benzocaine, Bumetanide, Carprofen,Carzenide, Diclofenac, Flufenamic acid, Furosemide, Iobenzamic acid,Iocetamic acid, and Mefenamic acid.

Examples of biologically active diamino compounds useful in the presentinvention include Amisulpride, Amodiaquine, Amosulalol, Amoxicillin,Amsacrine, Azacyclonol, Bromopride, Carvedilol, Cefprozil, Cinitapride,Clebopride, Clenbuterol, Ethoxzolamide, Nadoxolol, D-Norpseudoephedrine,amino acids (L-lysine), and natural products.

Examples of naturally occurring biologically active phenolics includebergaptol, caffeic acid, capsaicin, coumarin, daidzein,2,5-dihydroxy-benzoic acid, ferulic acid, flavonoids, glycitein(isoflavone), 4-hydroxycinnamic acid, 4-hydroxy-coumarin,isopimpinellin, resveratrol, synapic acid, vanillic acid, vanillin,chalcones, soybean flavonoids and derivatives thereof.

Capsaicin is a biologically active phenolic that is the active componentof cayenne pepper. The capsaicin is an amide of vanillylamine and C₈ toC₁₃ branched fatty acids. Topical application of capsaicin stimulatesand blocks small pain fibers by depleting them of the neurotransmittersubstance P that mediates pain impulses. A cream made from 0.025%-0.075%capsaicin applied 4× daily may help peripheral neuropathic pain,post-herpetic neuralgia, trigeminal neuralgia, psoriasis andfibromyalgia. It is also useful for diabetic neuropathy, clusterheadaches, earache, osteo- and rheumatoid arthritis. Capsaicin is apowerful pain reliever.

Naproxen, paracetamol, acetaminophen and acetylsalicylic acid arebiologically active phenolics that belong to the class of drugs callednon-steroidal anti-inflammatory drugs or NSAIDs. The NSAIDs providerelief by blocking the action of prostaglandins, which are hormone-likesubstances that contribute to pain, inflammation, fever and musclecramps. Phenolic moieties, synthetic and naturally occurring, are partof many drugs.

The compounds employed in the methods of the present invention may beprepared in a number of ways well known to those skilled in the art. Thecompounds may be synthesized, for example, by the methods describedbelow, or variations thereon as appreciated by the skilled artisan. Allprocesses disclosed in association with the present invention arecontemplated to be practiced on any scale, including milligram, gram,multigram, kilogram, multikilogram or commercial industrial scale.

The surgical articles, component thereof, polymeric carrier, or the likecan comprise a polymer formed by reacting an amine of one of theinvention with an isocyanate, carboxylic acid, activated carboxylicacid, or epoxide, or an isocyanate of the invention with an amine,alcohol, aminoalcohol, thiol or combination thereof, or a carboxylicacid of the invention with an alcohol, amine or combination thereof.

In another embodiment, the present invention is directed to theapplication of novel hydrolysable isocyanates, amines, biodegradable andbiocompatible polyurethanes and polyamides described in the presentpatent application, optionally in combination with those described inpatents/patent publications U.S. Pat. No. 7,772,352, US 2010/0260702 A1,US 2009/0292029 A1, US 2009/0082540, US 2006/0288547 A1, EP 1937182 B1,EP 2298235 A1, EP 1937182 A4, EP 1937182 A2, and WO 27030464 A2, all ofwhich have been assigned to Bezwada Biomedical, and U.S. Pat. No.4,829,099 assigned to Fuller, et al., for use in medicinal, medicaldevice, therapeutic, consumer product and cosmetic applicationsincluding but not limited to tissue engineering, foams (including butnot limited to reticulated foams, lyophilized foams and regular foams)for wound healing and drug delivery, bone hemostats and bone fillers,tissue adhesive and sealants, adhesion prevention barriers, meshes,filters, bone void fillers, controlled drug delivery, stents, medicaldevice coatings, pharmaceutical drug formulations, medical device,cosmetic and pharmaceutical packaging, apparels, infusion devices, bloodcollection tubes and devices, tubes, skin care and transdermal drugdelivery. The entire disclosures of all of the above-cited patents andpatent publications are incorporated by reference herein in theirentirety.

In another embodiment, the present invention is directed to absorbablepolyurethane foams with open and closed cell structures, including butnot limited to reticulated foams, foams with vertical channels,architecturally gradient foams, trans-compositional foams andtrans-structural foams and the process of preparing these absorbablefoams using the novel hydrolysable isocyanates, amines, biodegradableand biocompatible polyurethanes described in the present patentapplication, optionally in combination with those described inpatents/patent publications U.S. Pat. No. 7,772,352, US 2010/0260702 A1,US 2009/0292029 A1, US 2009/0082540, US 2006/0288547 A1, EP 1937182 B1,EP 2298235 A1, EP 1937182 A4, EP 1937182 A2, and WO 27030464 A2, all ofwhich are assigned to Bezwada Biomedical, and U.S. Pat. No. 4,829,099,assigned to Fuller, et al., via lyophilization wherein the absorbablepolyurethane polymers and/or blends thereof are dissolved in a suitablesolvent such as, without limitation, dioxane, N-methylpyrrolidone,dichloromethane and/or mixtures thereof, to form a homogeneous solutionwhich is subjected to a lyophilization process comprising a solution ofa bioabsorbable elastomer in a solvent which is substantially, but notnecessarily completely, solidified, then the solvent is removed fromthat which is lyophilized under reduced pressure to form a foam. Theentire disclosures of all of the above-cited patents and patentpublications are incorporated by reference herein in their entirety.

In another embodiment, isocyanates of the present invention provide atrue reticulated, flexible, resilient, bioabsorbable elastomeric matrix,suitable for implantation and having sufficient porosity to encouragecellular ingrowth and proliferation in vivo. The present invention alsoprovides a polymerization process for preparing an absorbablereticulated elastomeric matrix, the process comprising the steps of:

-   (1) admixing-   a) a polyol component,-   b) an isocyanate component,-   c) a blowing agent,-   d) optionally, a crosslinking agent,-   e) optionally, a chain extender,-   f) optionally, one or more catalysts,-   g) optionally, one or more cell openers,-   h) optionally, a surfactant, and-   i) optionally, a viscosity modifier;-   to provide a crosslinked elastomeric matrix, and reticulating the    elastomeric matrix by a reticulation process to provide the    reticulated elastomeric matrix.

The ingredients are present in quantities and the elastomeric matrix isprepared under conditions so as to:

-   (i) provide a crosslinked resiliently-compressible bioabsorbable    elastomeric matrix,-   (ii) control formation of biologically undesirable residues,    and (iii) reticulate the foam by a reticulation process, to provide    the reticulated elastomeric matrix.

In another embodiment, the invention is directed to a lyophilizationprocess for preparing a reticulated elastomeric matrix comprisinglyophilizing a flowable polymeric material. In another embodiment, thepolymeric material comprises a solution of a solvent-solublebioabsorbable elastomer in a solvent. In another embodiment, theflowable polymeric material is subjected to a lyophilization processcomprising solidifying the flowable polymeric material to form a solid,e.g., by cooling a solution, then removing the non-polymeric material,e.g., by evaporating the solvent from the solid under reduced pressure,to provide an at least partially reticulated elastomeric matrix. Inanother embodiment, a solution of a bioabsorbable elastomer in a solventis substantially, but not necessarily completely, solidified, then thesolvent is evaporated from that material to provide an at leastpartially reticulated elastomeric matrix. In another embodiment, thetemperature to which the solution is cooled is below the freezingtemperature of the solution. In another embodiment, the temperature towhich the solution is cooled is above the apparent glass transitiontemperature of the solid and below the freezing temperature of thesolution.

In another embodiment, the invention is directed to a lyophilizationprocess for producing an elastomeric matrix having a reticulatedstructure, the process comprising the steps of:

-   a) forming a solution comprising a solvent-soluble bioabsorbable    elastomer in a solvent;-   b) at least partially solidifying the solution to form a solid,    optionally by cooling the solution; and-   c) removing the non-polymeric material, optionally by evaporating    the solvent from the solid under reduced pressure, to provide an at    least partially reticulated elastomeric matrix comprising the    elastomer.

In another aspect of the present invention, the polymers of the presentinvention may contain a cleavable site which is preferably an ester siteand, more preferably, the cleavable ester site is adjacent one or moreamino acids. This provides segmented polyurethanes with cleavable sitesin its chain extender, which sites may be arranged to be recognizable byenzymes.

In another embodiment of the present invention, the inventive polymerscan be used as a pharmaceutical carrier in a drug delivery matrix. Thematrix is formed by mixing the polymer with a therapeutic agent. A vastvariety of different therapeutic agents can be used in conjunction withthe polymers of the invention. In general, therapeutic agentsadministered via the pharmaceutical compositions of the inventioninclude, without limitation antiinfectives such as antibiotics andantiviral agents; analgesics and analgesic combinations; anorexics;antihelmintics; antiarthritics; anti-asthmatic agents; anticonvulsants;antidepressants; antidiuretic agents; antidiarrheals; antihist-amines;antiinflammatory agents; antimigraine preparations; antinauseants;antineo-plastics; antiparkinsonism drugs; antipruritics; antipsychotics;antipyretics, antispas-modics; anticholinergics; sympathomimetics;xanthine derivatives; cardiovascular preparations including calciumchannel blockers and beta-blockers such as pindolol and antiarrhythmics;antihypertensives; diuretics; vasodilators including general coronary,peripheral and cerebral; central nervous system stimulants; cough andcold preparations, including decongestants; hormones such as estradioland other steroids, including corticosteroids; hypnotics;immunosuppressives; muscle relaxants; para-sympatholytics;psychostimulants; sedatives; tranquilizers; and naturally derived orgenetically engineered proteins, polysaccharides, glycoproteins orlipoproteins.

The drug delivery matrix may be administered in any suitable dosage formsuch as oral, parenteral, subcutaneously as an implant, vaginally or asa suppository. Matrix formulations containing polymers of the inventionis formulated by mixing one or more therapeutic agents with the polymer.The therapeutic agent may be present as a liquid, a finely dividedsolid, or any other appropriate physical form. Typically, the matrixwill include one or more additives, e.g., nontoxic auxiliary substancessuch as diluents, carriers, excipients, stabilizers or the like.However, the presence of such additives is entirely optional. Othersuitable additives may be formulated with the polymers of this inventionand pharmaceutically active agents or compounds, however, if water is tobe used it should be added immediately before administration.

The amount of therapeutic agent will be dependent upon the particulardrug employed and medical condition being treated. Typically, the amountof drug represents about 0.001% to about 70%, more typically about 0.01%to about 50%, and most typically about 0.1% to about 20% by weight ofthe matrix.

The quantity and type of polymer incorporated into a parenteral dosageform will vary depending on the release profile desired and the amountof drug employed. The product may contain blends of polymers of thisinvention to provide the desired release profile or consistency to agiven formulation.

The polymers of this invention, upon contact with body fluids includingblood or the like, undergoes gradual degradation (mainly throughhydrolysis) with concomitant release of the dispersed drug for asustained or extended period (as compared to the release from anisotonic saline solution). This can result in prolonged delivery (e.g.,over one to 2,000 hours, preferably two to 800 hours) of effectiveamounts (e.g., 0.0001 mg/kg/hour to 10 mg/kg/hour) of the drug. Thisdosage form can be administered as necessary depending on the subjectbeing treated, the severity of the affliction, the judgment of theprescribing physician, and the like.

Individual formulations of drugs and polymers of this invention may betested in appropriate in vitro and/or in vivo models to achieve thedesired drug release profiles. For example, a drug could be formulatedwith a polymer of this invention and orally administered to an animal.The drug release profile is monitored by appropriate means, such as bytaking blood samples at specific times and assaying the samples for drugconcentration. Following this or similar procedures, those skilled inthe art are able to formulate a variety of formulations having thedesired release profile.

The polyurethanes, polyureas, polyamideurethanes, and/orpolyureaurethanes of the invention may be formed into various articlesfor surgical and medical uses including, without limitation:

-   a. burn dressings, b. hernia patches, c. medicated dressings, d.    fascial substitutes, e. gauze, fabric, sheet, felt or sponge for    liver hemostasis, f. gauze bandages, g. arterial graft or    substitutes, h. bandages for skin surfaces, i. suture knot clip, j.    orthopedic pins, clamps, screws, and plates, k. clips (e.g., for    vena cava), l. staples, m. hooks, buttons, and snaps, n. bone    substitutes (e.g., mandible prosthesis), o. intrauterine devices    (e.g., spermicidal devices), p. draining or testing tubes or    capillaries, q. surgical instruments, r. vascular implants or    supports, s. vertebral discs, t. extracorporeal tubing for kidney    and heart-lung machines, and the like.

The polyurethanes, polyureas, polyamideurethanes, and/orpolyureaurethanes of the invention may be formed into surgical articlesusing any known technique, such as, for example, extrusion, moldingand/or solvent casting. The polyurethanes, polyureas,polyamideurethanes, and/or polyureaurethanes may be used alone, blendedwith other bioabsorbable compositions, or in combination withnon-bioabsorbable components. A wide variety of surgical articles may bemanufactured from the polyurethanes, polyureas, polyamideurethanes,and/or polyureaurethanes described herein. These include but are notlimited to clips and other fasteners, staples, sutures, pins, screws,prosthetic devices, wound dressings or coverings, burn dressings orcoverings, drug delivery devices, anastomosis rings, stents, stentcoatings, films, scaffolds, polyurethane foams, reticulated foams andother implantable medical devices. Examples of medical implantabledevices include prosthetic devices, stents, sutures, staples, clips andother fasteners, screws, pins, films, meshes, drug delivery devices orsystems, anastomosis rings, surgical dressings and the like. In somepreferred embodiments, the surgical articles or components thereofinclude stents, stent coatings, wound coverings, burn coverings, foams,tissue engineering scaffolds, films, implantable medical devices, and/orcontrolled drug delivery systems, more preferably stents, stentcoatings, wound and/or burn coverings, and/or controlled deliverysystems. In certain other preferred embodiments, the surgical articlesor components thereof include sutures, ligatures, needle and suturecombinations, surgical clips, surgical staples, surgical prostheticdevices, textile structures, couplings, tubes, supports, screws, orpins. In certain preferred drug delivery systems, the systems comprise apolyurethane, polyurea, polyamideurethane, and/or polyureaurethane inadmixture with a biologically or pharmaceutically active agent.Non-limiting examples of polymeric carriers in such drug deliverysystems and/or pharmaceutical compositions include self-supportingfilms, hollow tubes, beads, and/or gels. Other preferred uses of thesurgical articles include their use as scaffolds for tissue engineeringcomprising a porous structure for the attachment and proliferation ofcells.

Preferably, the surgical and medical uses of the filaments, films, andmolded articles of the present invention include, but are notnecessarily limited to knitted products, woven or non-woven, and moldedproducts including, burn dressings, hernia patches, medicated dressings,facial substitutes, gauze, fabric, sheet, felt or sponge for liverhomeostasis, gauze bandages, arterial graft or substitutes, bandages forskin surfaces, suture knot clip, orthopedic pins, clamps, screws, andplates, clips (e.g., for vena cava), staples, hooks, buttons, and snaps,bone substitutes (e.g., mandible prosthesis), bone void fillers, bonecements, intrauterine devices (e.g., spermicidal devices), draining ortesting tubes or capillaries, surgical instruments, vascular implants orsupports, vertebral discs, extracorporeal tubing for kidney andheart-lung machines, artificial skin and others.

The polyurethanes, polyureas, polyamideurethanes, and/orpolyureaurethanes disclosed herein may also be used to fabricatedegradable containers and packaging materials which can degrade inlandfills in contrast to existing non-degradable materials which presentenvironmental concerns.

The polyurethane material is believed to be especially useful for use asa tissue engineering scaffold, i.e., as a structure for the growth orregeneration of tissue. Polyurethanes may lend themselves to such usessince enzyme-catalyzed degradation may in some cases occur concurrentlywith the migration or growth of cells into the material, while desirablydegrading in the process into its substantially non-toxic constituents.It is also possible, in some cases, that cells migrating into or locatedadjacent the matrix may themselves exude proteolytic enzymes that willmediate hydrolytic cleavage.

Such tissue engineering scaffolds may have applications in theregeneration of skin and other organs, bone, cartilage, ligaments,tendons, bladder and other tissues. The polyurethane material may alsobe useful in the production of sutures, which require good mechanicalstrength, as well as in the production of drug release matrices, in viewof their need for degradation to non-toxic materials. The polyurethanematerial may also be useful for non-biomedical applications, wheredegradability into substantially non-toxic constituents is an asset. Thepolyurethane material lends itself to sterilization by such techniquesas gamma radiation and ethylene oxide treatments.

Fibers made from the present polyurethanes, polyureas,polyamideurethanes, and/or polyureaurethanes can be knitted or wovenwith other fibers, either bioabsorbable or non-bioabsorbable, to formmeshes or fabrics. Compositions including these polyurethanes,polyureas, polyamideurethanes, and/or polyureaurethanes may also be usedas bioabsorbable coatings for surgical devices.

Another aspect of the invention is directed to compositions containingthe polyurethanes, polyureas, polyamideurethanes, and/orpolyureaurethanes described herein which may be used to make reinforcedcomposites. Thus, for example, the polyurethane, polyurea,polyamideurethane, and/or polyureaurethane composition may form thematrix of the composite and may be reinforced with bioabsorbable ornon-bioabsorbable fibers or particles. Alternatively, a matrix of anybioabsorbable or non-bioabsorbable polymer composition may be reinforcedwith fibers or particulate material made from compositions containingthe polyurethanes, polyureas, polyamideurethanes, and/orpolyureaurethanes described herein.

In a further embodiment, the polyurethanes, polyureas,polyamideurethanes, and/or polyureaurethanes described herein may beadmixed with a filler. The filler may be in any particulate form,including granulate or staple fibers. While any known filler may beused, calcium carbonate, hydroxyapatite, tricalcium phosphate, bioglassor other bioceramics are the preferred fillers. Normally, from about 10grams to about 400 grams of filler are mixed with about 100 grams ofpolymer. The filled, cross-linked polymers are useful, for example, asmolding compositions.

It is further contemplated that one or more medico-surgically usefulsubstances may be incorporated into compositions containing thepolyurethanes, polyureas, polyamideurethanes, and/or polyureaurethanesdescribed herein. Examples of such medico-surgically useful substancesinclude, for example and without limitation, those which accelerate orbeneficially modify the healing process when particles are applied to asurgical repair site. For example, articles made from compositionscontaining the presently disclosed polyurethanes, polyureas,polyamideurethanes, and/or polyureaurethanes may carry a therapeuticagent which will be deposited at the repair site. The therapeutic agentmay be chosen for its antimicrobial properties, capability for promotingrepair or reconstruction and/or new tissue growth. Antimicrobial agentssuch as broad spectrum antibiotics, for example and without limitation,gentamycin sulfate, erythromycin, or derivatized glycopeptides which areslowly released into the tissue, may be applied in this manner to aid incombating clinical and sub-clinical infections in a tissue repair site.To promote repair and/or tissue growth, one or several growth promotingfactors may be introduced into the articles, e.g., fibroblast growthfactor, bone growth factor, epidermal growth factor, platelet -derivedgrowth factor, macrophage-derived growth factor, alveolar-derived growthfactor, monocyte-derived growth factor, magainin, and the like. Examplesof therapeutic indications include, without limitation, glycerol withtissue or kidney plasminogen activator to cause thrombosis, superoxidedismutase to scavenge tissue-damaging free radicals, tumor necrosisfactor for cancer therapy or colony stimulating factor and interferon,interleukin-2 or other lymphokine to enhance the immune system.

A further aspect of the invention is directed to monomers wherein theisocyanate groups are replaced with isothiocyanates; and polymersproduced therefrom. Specifically, this aspect of the invention isdirected to isothiocyanate analogs of all isocyanate monomers.

Another aspect of the invention is directed to more reactive isocyanatemonomers wherein the isocyanate(s) are prepared by reacting amino acidsand derivative thereof (including but not limited to nitrophenylalanine,aminophenyl alanine, amino tyrosines) with compounds containing aminobenzoic acid (para, meta, ortho), amino phenols (para, meta, ortho),amino salicylic acids (para, meta, ortho).

Another aspect of the invention is directed to more reactive isocyanatemonomers prepared by reacting aliphatic amino acids and/or amines(including but not limited to hexamethylene diamine, 1,4-butane diames)with compounds containing amino benzoic acid (para, meta, ortho), aminophenols (para, meta, ortho), amino salicylic acids (para, meta, ortho).Structures of selected examples of these isocyanates are given below

-   R1 is a residue of a diamine where in R1 is alkyl or aryl,    arylalkyl, with alkyl chains containing a primary (long) chain of 2    up to 24 chain atoms (not including H), or alkyl substituted with    analogs in which primary chain —CH₂— groups may be substituted with    —O—, or —S—, and wherein the primary chain and aryl can be    substituted with lower alkyl group(s) (such residue can be for    example a residue of a PEG polyol). R1 is also can be L-lysine or    aminophenyl alanine.

Another aspect of this invention is directed to amide acids by reactingamines and/or amino acids with unsymmetrical/symmetrical ether acids.Amines and amino acids include but are not limited to L-lysine,1,6-hexamethylene diamine, 1,4-butane diamine, aminophenyl alanine,L-tyrosine, amino tyrosine, nitrophenyl alanine, aminophenyl alanine,and unsymmetrical/symmetrical ether acids.

Another aspect of this invention includes polyamines and polyisocyanatesderived from nitrophenyl alanine. The structures of selected examplesthat represent these polyamines and polyisocyanates are given below

-   Where in Rn is residue of a diacid or residue of symmentrical or    unsymmentrical ether acids

The following examples are included to further illustrate the inventionand are not to be considered as limiting the invention anyway. Meltingpoints were measured for all products by using a Polmon (MP 96) meltingpoint apparatus. For all the products, NMR was run using a Varian 200MHz and tetramethylsilane as an internal standard.

EXAMPLES Example 1 Synthesis of L-Lysine Methyl Ester Dihydrochloride

To a mixture of L-Lysine-Hydrochloride (100 g) in 1.75 L of methanol at0° C. was bubbled dry HCl for 7 hours. The crude solid product wasfiltered, dried to get pure L-Lysine methyl ester dihydrochloride (117g, 91.6%) as a white powder with a melting point of 204.5-206° C. Thecompound was characterized by 1H NMR (DMSO-d₆) δ 1.48 (m, 2H, CH₂), 1.68(m, 2H, CH₂), 1.90 (m, 2H, CH₂), 2.80 (m, 2H, CH₂), 3.78 (s, 3H, Ester),4.00 (t, 1H, CH), 8.20 (bs, 2H, NH₂), 8.70 (bs, 2H, NH₂).

Example 2 Synthesis of Benzyloxy Carbonyl Methoxy-Acetic Acid

To a mixture of diglycolic acid (100 g), triethyl amine (136 ml) inAcetone (1000 ml) at 0° C. was added benzyl bromide (90 g) and stirredat room temperature for 20 hours. The reaction mixture was filtered toremove salts, distilled off acetone, poured onto 10% Sodium bicarbonatesolution (1000 ml), washed with Ethyl acetate (200 ml×3), aqueous phasemade acidic to pH 2 with dil Hydrochloric acid, extracted with ethylacetate, washed with water (600 ml), dried over Sodium sulphate,distilled under reduced pressure to give pure Benzyloxy carbonylmethoxy-acetic acid (80 g) as light yellow syrup. The compound wascharacterized by ¹HNMR (CDCl₃) δ 4.30 (s, 4H, CH₂ X₂), 5.25 (s, 2H,CH₂), 7.40 (m, 5H, Ar), 9.25 (bs, 1H, COOH).

Example 3 Synthesis of Chloro Carbonyl Methoxy-Acetic Acid Benzyl Ester

A solution of Benzyloxy carbonyl methoxy-acetic acid (40 g) and Thionylchloride (80 ml) was stirred at reflux temperature for 3 hours. ExcessThionyl chloride was distilled off, to the residue was added toluene(100 ml) and distilled off the solvent completely to get chloro carbonylmethoxy-acetic acid benzyl ester (40 g) as a light brown liquid whichwas used without further purification.

Example 4 Synthesis of2,6-Bis-(2-benzyloxycarbonylmethoxy-acetylamino)-hexanoic acid methylester

To a mixture of L-Lysine methyl ester dihydrochloride (30 g),Triethylamine (108 ml) in Ethyl acetate (750 ml) at 0° C. temperaturewas added chlorocarbonyl methoxy-acetic acid benzyl ester (77.7 g) dropwise, further stirred at room temperature for 10 hours. The solids werefiltered off; the organic phase was washed with 5% sodium bicarbonate(600 ml), water (600 ml), dried over sodium sulphate and distilled. Thecrude product was purified by column chromatography on silica gel usingHexane:Ethyl acetate (8:2) to get pure 2,6-Bis-[2-(2-benzyloxy carbonylmethoxy-ethoxy)-acetylamino]-hexanoic acid methyl ester (55 g) as alight brown syrup with 97% purity as determined by HPLC. The product wascharacterized by ¹H NMR (CDCl₃) δ 1.40 (m, 2H, CH₂), 1.50 (m, 2H, CH₂),1.60 (m, 2H, CH₂), 1.80 (m, 2H, CH₂), 3.30 (m, 1H, CH), 3.70 (s, 3H,ester), 4.10 to 4.20 (m, 8H, 4X CH₂), 4.60 (m, 1H, CH), 5.30 (s, 4H, 2XCH₂), 6.90 (bs, 1H, NH), 7.45 (m, 10H, Ar).

Example 5 Synthesis of 2,6-Bis-(2-carboxymethoxy-acetylamino)-hexanoicacid methyl ester

2,6-Bis-[2-(2-benzyloxy carbonyl methoxy-ethoxy)-acetylamino]-hexanoicacid methyl ester (6 g) was dissolved in Ethyl acetate (150 ml) in apressure vessel, palladium on carbon (5%, 50% wet, 2 g) added and themixture was stirred under an atmosphere of Hydrogen (5 kg) for 7 hoursat a temperature of 45-50° C. The catalyst was removed by filtration andethyl acetate was distilled off. The residue was washed with diisopropylether and solvents residue was removed by applying high vacuum to getpure 2,6-Bis-(2-carboxymethoxy-acetylamino) -hexanoic acid methyl ester(2.5 g) as light yellow syrup.

Example 6 Synthesis of polymer from2,6-Bis-(2-benzyloxycarbonylmethoxy-acetylamino) -hexanoic acid methylester

Into a clean flame dried 100 ml 4 neck round bottom flask equipped witha nitrogen inlet and a guard tube was added dibenzyl ester (15 g),PEG-1000 (26.22 g) and 10% Stannous octoate (2 ml) under nitrogenatmosphere. The reaction flask was placed in an oil bath with magneticstirring and having distillation condenser. The reaction mixture washeated to a temperature of 220° C. and maintained at the sametemperature for 3 hours. Benzyl alcohol formed was distilled off. Theflask was brought down to room temperature and high vacuum was applied.Reaction mixture was heated to a temperature of 100° C. and maintainedat the same temperature with high vacuum for 12 hours when the color ofthe reaction mixture changed to light brown thick syrup indicatingformation of polymer. 38 g of polymer formed was poured into glassbottle.

Example 7 Synthesis of (2-Benzyloxy carbonyl methoxy-ethoxy)-acetic acid

To a mixture of 3,6-Dioxaoctanoic acid (100 g), Triethylamine (131 g) inAcetone (1000 ml) at 0° C. was added Benzyl bromide (95.2 g) drop wise.The solution was further stirred at room temperature overnight. Thesolids were filtered off and acetone was distilled off. The residue wasdissolved in saturated sodium bicarbonate (1000 ml) and washed withethyl acetate. The aqueous phase was made acidic with HCl and extractedwith ethyl acetate (1500 ml) and dried over sodium sulphate anddistilled to get pure (2-Benzyloxy carbonyl methoxy-ethoxy)-acetic acid(80 grams) as a light yellow syrup.

Example 8 Synthesis of (2-Chlorocarbonylmethoxy-ethoxy)-acetic acidbenzyl ester

A solution of (2-Benzyloxy carbonyl methoxy-ethoxy)-acetic acid (40 g)and thionyl chloride (80 ml) was stirred at reflux temperature for 3hours. Excess thionyl chloride was distilled off and to the residue wasadded Toluene (100 ml). The solvent was distilled off completely toyield (2-Chlorocarbonylmethoxy-ethoxy)-acetic acid benzyl ester (40 g)as a light brown liquid which was used without further purification.

Example 9 Synthesis of 2-[2-(2-Benzyloxy carbonylmethoxy-ethoxy)-acetylamino]-3-(4-hydroxy-phenyl)-propionic acid ethylester

To a mixture of Tyrosine ethyl ester (20 g) and Triethylamine (20 ml) inEthyl acetate (300 ml) at 0° C. was added(2-Chlorocarbonylmethoxy-ethoxy)-acetic acid benzyl ester (28 g) dropwise. The solution was further stirred at room temperature for 36 hours.The solids were filtered off and the organic phase was washed with 5%sodium bicarbonate (200 ml) and water (200 ml). The organic phase wasdried over sodium sulphate and distilled. The crude was purified bycolumn chromatography on silica gel using Hexane:Acetone (7:3) to yieldpure 2-[2-(2-Benzyloxy carbonylmethoxy-ethoxy)-acetylamino]-3-(4-hydroxy-phenyl)-propionic acid ethylester (20 g) as a light brown syrup. The product was characterized by

HPLC: 99% and ¹H NMR (CDCl₃) δ 1.20 (t, 3H, CH₃), 2.90 to 3.10 (m, 2H,CH₂), 3.60 (m, 4H, 2X CH₂), 3.90 (s, 2H, CH₂), 4.10 (m, 4H, 2X CH₂),4.85 (m, 1H, CH), 5.20 (s, 2H, CH₂), 6.70 (d, 2H, Ar), 7.00 (d, 2H, Ar),7.45 (m, 6H, NH & Ar).

Example 10 Synthesis 2-[2-(2-Carboxymethoxy-ethoxy)-acetylamino]-3-(4-hydroxy-phenyl)-propionic acid ethylester

2-[2-(2-Benzyloxy carbonylmethoxy-ethoxy)-acetylamino]-3-(4-hydroxy-phenyl)-propionic acid ethylester (5 g) was dissolved in ethyl acetate (200 ml) in a pressurevessel. Palladium on carbon (5%, 50% wet, 2 g) was added and the mixturewas stirred under an atmosphere of hydrogen (6 kg) for 9 hours at atemperature of 45-50° C. The catalyst was removed by filtration anddistilled off ethyl acetate and the residue was washed with Diisopropylether and solvents residue was removed by applying high vacuum to getpure 2-[2-(2-Carboxy methoxy-ethoxy)-acetylamino]-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (2.2 g) as light yellow syrup. The productwas characterized by ¹H NMR which showed the presence of some impuritiesand hence was purified by column chromatography.

Example 11 Synthesis of polymer from 2-[2-(2-Benzyloxy carbonylmethoxy-ethoxy) -acetylamino]-3-(4-hydroxy-phenyl)-propionic acid ethylester

Into a clean flame dried 100 ml 4 neck round bottom flask equipped withN₂ bubbler and guard tube was charged dibenzyl ester (6 g), PEG-1000(13.10 g) and 10% stannous octoate (1 ml) under nitrogen atmosphere. Theflask was placed in an oil bath with magnetic stirring and havingdistillation condenser. Reaction mixture was heated to a temperature of210 to 220° C. and maintained at the same temperature for 4 hours whendistillation of Benzyl alcohol was observed which was confirmed by TLC.Further heating was cut off and at room temperature high vacuum wasapplied. Reaction mixture was kept at a temperature of 80 to 100° C. andmaintained at the same temperature with high vacuum for 8 hours.Reaction mixture was changed to light brown thick syrup indicatingformation of polymer. 18 g of Reaction mixture poured into glass bottle.

Example 12 Synthesis of {[6-(2-Carboxymethoxy-acetylamino)-hexylcarbamoyl]-methoxy}-acetic acid

To a solution of Diglycolic anhydride (30 g) in Dimethylformamide (85ml) at 60° C. was added dropwise a solution of 1,6-Hexamethylene diamine(11.6 g) in Dimethylformamide (50 ml). The reaction mixture was stirredat the same temperature for 1 hour. The reaction mixture was cooled to0° C. and maintained for 3 hours. The solid was filtered and washed withchloroform and dried to get pure {[6-(2-Carboxy methoxy-acetylamino)-hexylcarbamoyl]-methoxy}-acetic acid (9 g) as white powder with amelting point of 178-180° C. The compound was characterized by ^(I)H NMR(DMSO-d₆) δ1.25 (m, 2H, CH₂), 1.55 (m, 2H, CH₂), 2.80 (m, 2H, CH₂), 3.90(s, 4H, 2X CH₂), 7.90 (bs, 1H, NH).

Example 13 Synthesis of(2-Chloro-N-[6-(2-chloro-acetylamino)-hexyl]-acetamide)

To a mixture of 1,6-Hexamethylene diamine (150 g) and Sodium bicarbonate(645 g) in ethyl acetate (2500 ml) at 0° C. was added dropwisechloroacetyl chloride (257 ml). The reaction mixture was further stirredat room temperature for 1 hour followed by heating to 55° C. andmaintained for 6 hours. The solvent was distilled off and the residuewas taken into cold water. The filtered solid was separated and purifiedby recrystallisation from ethyl acetate to get pure(2-Chloro-N-[6-(2-chloro-acetylamino)-hexyl]-acetamide) (200 g) as whitepowder with a melting point of 134.5-136.7° C. The compound wascharacterized by ^(I)H NMR (DMSO-d₆) δ 1.24 (m, 2H, CH₂), 1.42 (m, 2H,CH₂), 3.06(m, 2H, CH₂), 4.02(s, 2H, CH₂), 8.19(bs, 1H, NH).

Example 14 Synthesis of (Benzyloxy-acetic acid {6-[2-(2-benzyloxy-acetoxy)acetylamino]-hexylcarbamoyl}-methyl ester)

To a solution of 2-Chloro-N-[6-(2-chloro-acetylamino)-hexyl]-acetamide(200 gm) and triethyl amine (400 ml) in Acetone (2000 ml) at roomtemperature was added dropwise Benzyloxy acetic acid (350 g). Thesolution was further stirred at reflux temperature overnight. Thereaction mixture was poured onto cold water and solids were filtered,dried and the crude product was purified by recrystallisation from Ethylacetate to yield pure (Benzyloxy-aceticacid-{6-[2-(2-benzyloxy-acetoxy)-acetylamino]-hexylcarbamoyl}-methylester) (190 g) as white powder with a melting point of 101-103° C. Theproduct was characterized by ^(I)H NMR (CDCl₃+DMSO-d₃) δ 1.24 (m, 2H,CH₂), 1.43 (m, 2H, CH₂), 3.15 (t, 2H, CH₂), 4.15 (s, 2H, CH₂), 4.48 (s,2H, CH₂), 4.56 (s, 2H, CH₂), 7.30 (m, 5H, Ar), 7.46 (t, 1H, NH).

Example 15 Synthesis of (Hydroxy-acetic acid {6-[2-(2-hydroxy-acetoxy)-acetylamino]-hexylcarbamoyl}-methyl ester)

Benzyloxy-acetic acid {6-[2-(2-benzyloxy-acetoxy)-acetylamino]-hexylcarbamoyl}-methyl ester (250 g) was dissolved in DMF (600ml) in a pressure vessel (Autoclave), 50% wet palladium on carbon (10%,75 g) was added and the mixture was stirred under hydrogen atmosphere (8Kg) for 72 hours at 70° C. The catalyst was removed by filtration and80% of the DMF was distilled off. The crude product was precipitated byadding to Methanol and filtered and dried to get pure (Hydroxy-aceticacid {6-[2-(2-hydroxy -acetoxy)-acetylamino]-hexylcarbamoyl}-methylester) (90 g) as a white powder with a melting point of 156-158° C. Thepure product was characterized by ^(I)HNMR (CDC1₃+DMSO-d₆) δ 1.22 (m,2H, CH₂), 1.38 (m, 2H, CH₂), 3.06 (m, 2H, CH₂), 4.15 (d, 2H, CH₂), 4.48(s, 2H, CH₂), 5.42 (t, 1H, OH), 7.98 (bt, 1H, NH).

Example 16 Synthesis of Benzyloxy Carbonyl Methoxy-Acetic Acid

To a mixture of Diglycolic acid (100 g), Triethyl amine (136 ml) inAcetone (1000 ml) at 0° C. was added Benzyl bromide (90 g). The solutionwas stirred at room temperature for 20 hours. The reaction mixture wasfiltered to remove salts and acetone was distilled off. The reactionmixture was poured onto 10% Sodium bicarbonate solution (1000 ml),washed with Ethyl acetate (600 ml). The aqueous phase was made acidic topH 2 with dilute Hydrochloric acid. The organic compound was extractedwith ethyl acetate and washed with water (600 ml) and dried over sodiumsulphate. The organic solvent was distilled under reduced pressure togive pure Benzyloxy carbonyl methoxy-acetic acid (80 g) as light yellowsyrup. The compound was characterized by ^(I)HNMR (CDCl₃) δ 4.30 (s, 4H,CH₂X2), 5.25 (s, 2H, CH₂), 7.40 (m, 5H, Ar), 9.25 (bs, 1H, COOH).

Example 17 Synthesis of Chloro Carbonyl Methoxy-Acetic Acid Benzyl Ester

A solution of Benzyloxycarbonyl methoxy-acetic acid (40 g) and ThionylChloride (80 ml) was stirred at reflux temperature for 3 hours. ExcessThionyl Chloride was distilled off and to the residue was added Toluene(100 ml). The solvent was distilled off completely to get chlorocarbonylmethoxy-acetic acid benzyl ester (40 g) as a light brown liquid whichwas used without further purification.

Example 18 Synthesis of 2-(2-Benzyloxy carbonylmethoxy-acetylamino)-3-(4-hydroxy-phenyl)-propionic acid ethyl ester

To a mixture of Tyrosine ethyl ester (40 g) and Triethylamine (40 ml) inEthyl acetate (600 ml) at 0° C. temperature was added Chloro carbonylmethoxy-acetic acid benzyl ester (46.5 g) drop wise. The reactionmixture was further stirred at room temperature for 10 hours. The solidswere filtered off and the organic phase was washed with 5% sodiumbicarbonate solution (600 ml) and water (600 ml). It was dried oversodium sulphate and organic solvent was distilled. The crude waspurified by column chromatography on silica gel using Hexane:Ethylacetate (8:2) to get pure 2-(2-Benzyloxy carbonyl methoxy-acetylamino)-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (30 g) as a lightyellow syrup. The product was characterized by ¹H NMR (CDCl₃) δ 1.20 (t,3H, CH₃), 2.90 to 3.10 (m, 2H, CH₂), 4.10 to 4.30 (m, 6H, 3X CH₂), 4.85(q, 1H, CH), 5.20 (s, 2H, CH₂), 5.80 (bs, 1H, NH), 6.70 (d, 2H, Ar),7.00 (d, 2H, Ar), 7.40 (m, 5H, Ar).

Example 19 Synthesis of 2-(2-Carboxymethoxy-acetylamino)-3-(4-hydroxy-phenyl) -propionic acid ethyl ester

2-(2-Benzyloxy carbonyl methoxy-acetyl amino)-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (6 g) was dissolved in Ethyl acetate (150ml) in a pressure vessel, palladium on carbon (5%, 50% wet, 2 g) addedand the mixture stirred under an atmosphere of Hydrogen (5 kg) for 7hours at a temperature of 45-50° C. The catalyst was removed byfiltration and Ethyl acetate was distilled off and the residue waswashed with diisopropyl ether and solvent residue was removed byapplying high vacuum to get pure 2-(2-Carboxymethoxy-acetylamino)-3-(4-hydroxy-phenyl)-propionic acid ethyl ester(2.5 grams) as light yellow syrup. The product was characterized by ¹HNMR which showed the presence of some impurities and hence was purifiedby column chromatography.

Example 20 Synthesis of polymer from 2-(2-Benzyloxy carbonylmethoxy-acetylamino)-3-(4-hydroxy-phenyl)-propionic acid ethyl ester

A clean flame dried 100 ml 4 neck RB flask equipped with N₂ bubbler andguard tube was placed in a oil bath with magnetic stirring and havingdistillation condenser. Into this flask was added Dibenzyl ester (15 g)and PEG-1000 (26.22 g) and 10% stannous octoate (2 ml) under nitrogenatmosphere. Reaction mixture was heated to a temperature of 220° C. andmaintained at the same temperature for 4 hours. During the processBenzyl alcohol was distilled as confirmed by the TLC. Heating was cutoff and at room temperature high vacuum was applied. Reaction mixturewas heated to a temperature of 100° C. and maintained at the sametemperature with high vacuum for 10 hours. Reaction mixture was changedto light brown thick syrup indicating formation of polymer. 31 g ofReaction mixture poured into glass bottle.

Example 21 Synthesis of L-Lysine Methyl Ester Dihydrochloride

A mixture of L-Lysine-Hydrochloride (100 g) in methanol (1.75 lit) at 0°C. was bubbled dry HCl for 7 hours. The crude solid product was filteredand dried to get pure L -Lysine methyl ester dihydrochloride (117 g) asa white powder with a melting point of 204.5-206° C. The product wascharacterized by ¹H NMR (DMSO-d₆) δ 1.48 (m, 2H, CH₂), 1.68 (m, 2H,CH₂), 1.90 (m, 2H, CH₂), 2.80 (m, 2H, CH₂), 3.78 (s, 3H, Ester), 4.00(t, 1H, CH), 8.20 (bs, 2H, NH₂), 8.70 (bs, 2H, NH₂).

Example 22 Synthesis of (2-Benzyloxy carbonyl methoxy-ethoxy)-aceticacid

To a mixture of 3,6-Dioxaoctanoic acid (100 g), Triethylamine (131 g) inAcetone (1000 ml) at 0° C. temperature was added Benzyl bromide (95.2 g)drop wise. The solution was left for stirring overnight. The solids werefiltered off and acetone was distilled off. The residue was dissolved insaturated sodium bicarbonate (1000 ml), and washed with Ethyl acetate.The aqueous phase was made acidic with HCl and extracted with Ethylacetate (1500 ml). The organic layer was dried over sodium sulphate andthe solvent was distilled off to yield pure (2-Benzyloxy carbonylmethoxy-ethoxy)-acetic acid (80 g) as a light yellow syrup.

Example 23 Synthesis of (2-Chlorocarbonylmethoxy-ethoxy)-acetic acidbenzyl ester

A solution of (2-Benzyloxy carbonyl methoxy-ethoxy)-acetic acid (40 g)and Thionyl Chloride (80 ml) was stirred at reflux temperature for 3hours. Excess Thionyl Chloride was distilled off and to the residue wasadded Toluene (100 ml). The solvent was distilled off completely to get(2-Chlorocarbonylmethoxy-ethoxy)-acetic acid benzyl ester (40 g) as alight brown liquid which was used without further purification.

Example 24 Synthesis of 2,6-Bis-[2-(2-benzyloxy carbonyl methoxy-ethoxy)-acetylamino]-hexanoic acid methyl ester

To a mixture of L-Lysine methyl ester dihydrochloride (10 g) andTriethylamine (36 ml) in Ethyl acetate (750 ml) at 0° C. temperature wasadded (2-Chlorocarbonylmethoxy-ethoxy)-acetic acid benzyl ester (40 g)drop wise. The solution was further stirred at room temperature for 16hours. The solids were filtered off and the organic phase was washedwith 5% sodium bicarbonate (200 ml) solution and water (200 ml). It wasdried over sodium sulphate and organic layer was distilled off. Thecrude product was purified by column chromatography on silica gel usingHexane:Acetone (8:2) to get pure 2,6-Bis-[2-(2-benzyloxy carbonylmethoxy-ethoxy)-acetylamino]-hexanoic acid methyl ester (17 g) as alight yellow syrup. The product was characterized by HPLC: 98.5% and ¹HNMR (CDCl₃) δ 1.40 (m, 2H, CH₂), 1.55 (m, 2H, CH₂), 1.70 (m, 2H, CH₂),1.90 (m, 2H, CH₂), 3.30 (m, 1H, CH), 3.65 (m, 11H, Ester and 4CH₂), 4.00(m, 4H, 2X CH₂), 4.20 (m, 4H, 2X CH₂), 4.60 (m, 1H, NH), 5.20 (s, 4H, 2XCH₂), 7.10 (bs, 1H, NH), 7.40 (m, 10H, Ar).

Example 25 Synthesis of 2,6-Bis-[2-(2-carboxymethoxy-ethoxy)-acetylamino]-hexanoic acid methylester

2,6-Bis-[2-(2-benzyloxy carbonyl methoxy-ethoxy)-acetylamino]-hexanoicacid methyl ester (7 g) was dissolved in Ethyl acetate (200 ml) in apressure vessel, palladium on carbon (5%, 50% wet, 3 g) added and themixture stirred under an atmosphere of Hydrogen (5 kg) for 8 hours at atemperature of 45-50° C. The catalyst was removed by filtration andethyl acetate was distilled off. The residue was washed with diisopropylether and solvent residue was removed by applying high vacuum to getpure 2,6-Bis-[2-(2-carboxy methoxy-ethoxy)-acetylamino]-hexanoic acidmethylester (3 g) as light yellow syrup. The product was characterizedby ¹H NMR which showed the presence of some impurities and hence waspurified by column chromatography.

Example 26 Synthesis of polymer from 2,6-Bis-[2-(2-benzyloxy carbonylmethoxy -ethoxy)-acetylamino]-hexanoic acid methyl ester

A clean flame dried 100 ml 4 neck RB flask equipped with N₂ bubbler andguard tube was placed in a oil bath with magnetic stirring and havingdistillation condenser. Into the flask were added dibenzyl ester (5 g),PEG-1000 (7.6 g) and 10% stannous octoate (1 ml) under nitrogenatmosphere. The reaction mixture was heated to a temperature of 210 to220° C. and maintained at the same temperature for 4 hours. During theprocess ˜0.5 ml of Benzyl alcohol was distilled off. The heating was cutoff. At room temperature high vacuum was applied. Reaction mixture washeated to a temperature of 80 to 100° C. and maintained at the sametemperature under high vacuum for 8 hours. Reaction mixture was changedto light brown thick syrup indicating formation of polymer. 10 grams ofreaction mixture was poured into glass bottle

Example 27 Diisocyanate from 4-Nitrophenylalanine Stearyl Ester

2-Isocyanato-3-(4-isocyanato-phenyl)-propionic acid Stearyl ester isprepared using the following Scheme-I:

The above crude DiNCO was recrystllised from Toluene/Hexane and isolated7 grams of the pure product as white powder with a MP of 58-60° C. andconfirmed by NMR and IR.

Example 28 Diisocyanate from 4-Nitrophenylalanine 4-NitroBenzoic acidMethyl Ester

2-(4-Isocyanato-benzoylamino)-3-(4-isocyanato-phenyl)-propionic acidmethyl ester is prepared using the following scheme-II

The above 35 grams of the Amine from the first batch was converted toDiNCO, reaction has progressed by TLC, and isolated 35 grams of a sampleas light brown syrup. The crude product has only 81% NCO by titration.After putification, it has 99% therotical NCO.

Example 29 Triisocyanate from 4-Nitrophenylalanine 4-NitroBenzoic acid4-Nitro phenol

2-(4-Isocyanato-benzoylamino)-3-(4-isocyanato-phenyl)-propionic acid4-isocyanato-phenyl ester is prepared using the following Scheme-III:

Example 30 Tetraisocyanate from 4-Nitrophenylalanine Ethylene GlycolLactate Linker

2-Isocyanato-3-(4-isocyanato-phenyl)-propionic acid1-(2-{2-[2-isocyanato-3-(4-isocyanato-phenyl)-propionyloxy]-propionyloxy}-ethoxycarbonyl)-ethylester is prepared using the following Scheme-IV:

Example 31 Synthesis of 4-Nitro Phenyl Alanine Methyl EsterHydrochloride

To a mixture of 4-nitro phenyl alanine (15 g) and DMAP (2.12 g) inmethanol (150 ml) at 0° C. was added thionyl chloride (7.8 g) dropwiseand later heated to reflux for 5 hours. The solvent was distilled offunder vacuum. The solid separated was filtered and purified fromMethanol and Diisopropyl ether to yield 4-nitrophenylalanine methylester hydrochloride (12 g) as white powder with a melting point of218-220° C. and a purity of 99% as determined by HPLC.

Example 32 Synthesis of3-(4-nitro-phenyl)-2-(4-nitro-benzoylamino)-propionic acid methyl ester

To a mixture of 4-nitro phenyl alanine methyl ester hydrochloride (250g) and triethylamine (320 ml) maintained at 0° C. in dimethylformamide(1250 ml) under nitrogen atmosphere was added dropwise 4-nitro benzoylchloride (143 g) and allowed to slowly come to room temperature followedby further stirring for 2 hours. The reaction mixture was poured ontocold water and the precipitated solid was filtered off, dried andrecrystallized from mixture of dimethylformamide:methanol (2:1) to yieldpure 3-(4-nitro -phenyl)-2-(4-nitro-benzoylamino)-propionic acid methylester (260g) as light brown powder with a melting point of 237-239° C.The product was characterized by IH NMR (DMSO-d₆) δ 3.10-3.30 (m, 2H,CH2), 3.60 (s, 3H, OCH3), 4.80 (m, 1H, CH), 7.50 (d, 2H, Ar), 8.00 (d,2H, Ar), 8.10 (d, 2H, Ar), 8.25 (d, 2H, Ar), 9.20 (d, 1H, NH)

Example 33 Synthesis of3-(4-Amino-phenyl)-2-(4-amino-benzoylamino)-propionic acid methyl ester

3-(4-nitro-phenyl)-2-(4-nitro-benzoylamino)-propionic acid methyl ester(80 g) was dissolved in a mixture of dimethylformamide: ethyl acetate(2.5:7.5; 2400 ml) in a pressure vessel. 10% Palladium carbon (30 grams,50% wet) was added and the reaction mixture was stirred under anatmosphere of hydrogen (5 Kg) at 50° C. for 5 hours. The temperature ofthe reaction mixture was brought to 20° C. and the catalyst was removedby filtration. The solvent was distilled off and the diamine wasprecipitated by adding diisopropyl ether (500 ml) and methanol (50 ml).The solid diamine was filtered and dried to yield pure2-Amino-3-(4-amino-phenyl)-propionic acid octadecyl ester (55 g) as offwhite powder with a melting point of 178-180° C. and a purity of 99% asdetermined by HPLC. The diamine was further characterized by IH NMR(CDCl3+DMSO-d6) δ 2.90-3.00 (m, 2H, CH2), 3.60 (s, 3H, OCH3), 4.30 (bs,2H, NH2), 4.50 (m, 1H, CH), 5.10 (bs, 2H, NH2), 6.50 (m, 4H, Ar), 6.90(d, 2H, Ar), 7.50 (d, 2H, Ar), 7.70 (d, 1H, NH)

Example 34 Synthesis of3-(4-Isocyanato-phenyl)-2-(4-Isocyanato-benzoylamino) -propionic acidmethyl ester

Into a solution of 2-Amino-3-(4-amino-phenyl)-propionic acid octadecylester (100 g) in dry 1,4-dioxane (2000 ml) under Nitrogen atmospheremaintained at 20° C. was added a solution of triphosgene (163 g) in1,4-Dioxane (200 ml) in one lot. The reaction mixture was heated andrefluxed for 3 hours. The condenser was then arranged for distillationand solvent removed by distillation at atmospheric pressure until thevolume of the reaction mixture was reduced to approximately one third.Fresh dry dioxane (200 ml) was added and distilled off under vacuum. Theresidue was dissolved in Toluene (200 ml) and charcoal (5 g) was added.The solution was filtered hot and the solvent was distilled under vacuumto yield crude diisocyanate which was again dissolved in a mixture oftoluene:hexane (6:4; 400 ml) by heating to 80° C. for 15 minutes. Thesolution was filtered and the solvent mixture was distilled off undervacuum. Hexane was added to the precipitate and pure diisocyanate wasfiltered, dried and packed in tight container to yield 65 g of pure2-Isocyanato-3-(4-Isocyanato-phenyl)-propionic acid octadecyl ester as awhite powder with a melting point of 78-80° C. The product was furthercharacterized by IR: 2261 cm⁻¹ and IH NMR (CDCl₃) δ 3.15-3.30 (m, 2H,CH2), 3.70 (s, 3H, OCH3), 5.05 (m, 1H, CH), 6.60 (d, 1H, NH), 7.00 (d,2H, Ar), 7.05 (d, 2H, Ar), 7.15 (d, 2H, Ar), 7.60 (d, 2H, Ar)

Example 35 Synthesis of2-Benzyloxycarbonylamino-3-(4-nitro-phenyl)-propionic acid

To a mixture of 4-nitro phenyl alanine (500 g), sodium hydroxide (162 g)and water (5000 ml) maintained at 0 to 5° C., was added drop wise 50%benzyl chloroformate in toluene (977 g). The reaction mixture wasallowed to slowly come to room temperature and further stirredovernight. The reaction mixture was cooled to 10° C. and the pH wasadjusted to 2 with dilute HCl. The residue precipitated was filtered anddried to yield pure2-Benzyloxycarbonylamino-3-(4-nitro-phenyl)-propionic acid (600 g) as anoff white powder with a melting point of 123-127° C. The product wascharacterized by IH NMR (CDCl3+DMSO-d6) δ 3-3.20 (m, 2H, CH2), 4.30 (m,1H, CH), 4.90 (s, 2H, CH2), 7.20 (m, 6H, Ar & NH), 7.40 (d, 2H, Ar),8.05 (d, 2H, Ar)

Example 36 Synthesis of2-Benzyloxycarbonylamino-3-(4-nitro-phenyl)-propionic acid Stearyl ester

To a mixture of 2-benzyloxycarbonylamino-3-(4-nitro-phenyl)-propionicacid (400 g), potassium carbonate (192.5 g) in NMP (1460 ml) maintainedat 20° C., was added dropwise 1-Bromo octadecane (425 g). The reactionmixture was allowed to slowly come to room temperature and furtherstirred for 24 hours. The reaction mixture was then poured onto icewater and the pH was adjusted to 7 with dilute HCl. The solid wasfiltered, dried and purified by column chromatography using hexane:ethylacetate (95:5) as an eluant to yield pure2-benzyloxycarbonylamino-3-(4-nitro-phenyl)-propionic acid stearyl ester(430 g) as a white powder with a melting point of 56-59° C. The productwas further characterized by IH NMR (CDCl₃) δ 0.90 (t, 3H, CH3), 1.30(m, 30H, 15X CH2), 1.60 (m, 2H, CH2), 3.05-3.25 (m, 2H, CH2), 4.20 (m,2H, CH2), 4.65 (m, 1H, CH), 5.15 (m, 2H, CH2), 5.40 (d, 1H, NH), 7.30(m, 54H, Ar), 7.45 (d, 2H, Ar), 8.15 (d, 2H, Ar)

Example 37 Synthesis of 2-Amino-3-(4-amino-phenyl)-propionic acidoctadecyl ester

2-Benzyloxycarbonylamino-3-(4-nitro-phenyl)-propionic acid Stearyl Ester(430 g) was dissolved in ethyl acetate (2500 ml) in a pressure vessel.10% Palladium carbon (58 g, 50% wet) was added and the reaction mixturewas stirred under an atmosphere of Hydrogen (10 Kg) at 50° C. for 12hours. The reaction mixture was brought to 20° C. and the catalyst wasremoved by filtration. The solvent was distilled off and the resultingdiamine was precipitated by adding hexane. It was filtered and dried toyield pure 2-amino-3-(4-amino -phenyl)-propionic acid octadecyl ester(200 g) as a white powder with a melting point of 54-56° C. and a purityof 98% as determined by HPLC. The product was further characterized byIH NMR (CDCl₃) δ 0.90 (t, 3H, CH3), 1.25 (m, 30H, 15X CH2), 1.65 (m, 2H,CH2), 2.90-3.05 (m, 2H, CH2), 3.70 (m, 1H, CH), 4.00-4.15 (m, 6H, 2X NH2& CH2), 6.60 (d, 2H, Ar), 6.95 (d, 2H, Ar)

Example 38 Synthesis of 2-Isocyanato-3-(4-isocyanato-phenyl)-propionicacid octadecyl ester

To a solution of 2-Amino-3-(4-amino-phenyl)-propionic acid octadecylester (100 g) in dry 1,4-dioxane (800 ml) maintained under nitrogenatmosphere at 10° C. was added a solution of triphosgene (116 g) in1,4-dioxane (300 ml) in one lot. The reaction mixture was refluxed for 2hours. The condenser was then arranged for distillation and solvent wasremoved by distillation at atmospheric pressure until the volume of thereaction mixture was reduced to approximately one third. Fresh dryDioxane (300 ml) was added and the solvents were distilled off undervacuum. The residue was dissolved in toluene (300 ml) and then thetoluene was distilled off. Fresh toluene (300 ml) was added along withcharcoal (10 g) and the solution was filtered hot. The toluene wasdistilled off under vacuum to yield crude diisocyanate. Thisdiisocyanate was kept in the freezer overnight. The disocyanate waspurified via trituration and recrystallization using hexane (200 ml) toyield solid diisocyanate which was cooled to 0-5° C. and left for 30minutes under nitrogen. The pure diisocyanate was filtered, dried andpacked in tight container to yield2-Isocyanato-3-(4-isocyanato-phenyl)-propionic acid octadecyl ester. Theproduct was characterized by IH NMR (CDCl₃) δ 0.90 (t, 3H, CH3), 1.30(m, 30H, 15X CH2), 1.65 (m, 2H, CH2), 3.00-3.20 (m, 2H, CH2), 4.20 (m,3H, CH & CH2), 7.05 (d, 2H, Ar), 7.15 (d, 2H, Ar)

Example 39 Synthesis of polyurethane polymer from 4-nitrophenyl alaninestearyl diisocyanate

Into a clean flame dried 250 ml cylindrical flask equipped with nitrogeninlet and placed in an oil bath with mechanical stirrer was addedpluronic-F-68 (86.8 g) under nitrogen. The temperature of the bath wasincreased upto 75-80° C. Once the Pluronic-F-68 melted, the temperatureof the bath was lowered down to 60° C. Diisocyanate (10 g) was added tothe pluronic while the bath temperature was maintained at 60° C. Thereaction mixture was stirred at the same temperature for 2 hoursfollowed by the addition of 1,4Butanediol (1.9 g) and 0.5 ml 10%Stannous octoate catalyst solution in toluene. The reaction mixturebecame viscous syrup and was stirred at 60° C. for 2 hours. A second lotof a solution of 1,4-butanediol (0.4 g) in 1 ml dimethylacetamide and10% stannous octoate catalyst in toluene 0.5 ml was added into thereaction mixture and left for stirring at the same temperature for 2hours. The reaction mixture was then poured on to a petri dish and keptin a vacuum oven for 24 hours to yield 87 grams of off white colorpolyurethane polymer.

Example 40 Synthesis of polyurethane polymer from 4-nitrophenyl alaninebenzoic acid diisocyanate

Into a clean flame dried 500 ml cylindrical flask equipped with nitrogeninlet and placed in an oil bath with mechanical stirrer was addedpluronic-F-127 (172.6 g) under nitrogen. The temperature of the bath wasincreased upto 140-145° C. Once the Pluronic-F-127 melted, thetemperature of the bath was lowered down to 60° C. Diisocyanate (5 g)was added to the pluronic while the bath temperature was maintained at60° C. The reaction mixture was stirred at the same temperature for 2hours followed by the addition of 1,4Butanediol (1.9 g) and 0.5 ml 10%Stannous octoate catalyst solution in toluene. The reaction mixturebecame viscous syrup when stirred at 60° C. for 2 hours. The reactionmixture was then poured on to a petri dish and kept in a vacuum oven for24 hours to yield 150 grams of pale yellow color polyurethane polymer.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. All ranges recited herein includeranges therebetween, and can be inclusive or exclusive of the endpoints.Optional included ranges can be from integer values therebetween, at theorder of magnitude recited or the next smaller order of magnitude. Forexample, if the lower range value is 0.2, optional included endpointscan be 0.3, 0.4, . . . 1.1, 1.2, and the like, as well as 1, 2, 3 andthe like; if the higher range is 8, optional included endpoints can be7, 6, and the like.

Numbered, Exemplary Embodiments

The invention includes the following embodiments E1 to E29:

E1. Absorbable Amines of the Formula A:

Wherein:

-   Each X is independently selected from:-   —OCH₂CO— (glycolic ester moiety)-   —OCH(CH₃)CO— (lactic ester moiety)-   —OCH₂CH₂OCH₂CO— (dioxanone ester moiety)-   —OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone ester moiety);-   —O(CH₂)_(y)CO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —O(CH₂CH₂O)_(m)CH₂CO—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   Each X′ is independently selected from:-   —CH₂COO— (glycolic moiety)-   —CH(CH₃)COO— (lactic moiety)-   —CH₂CH₂OCH₂COO— (dioxanone moiety)-   —CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety)-   —(CH₂)_(y)COO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —(CH₂CH₂O)_(m)CH₂COO—; where m is integer between 2-24 inclusive;    and,-   R is a residue of an amino acid including but not limited to    alanine, asparagine, aspartic acid, gamma amino butyric acid,    glycine, glutamic acid, valine, lysine, isoleucine, leucine,    tyrosine, ornithine, phenylalanine and sarcosine, 3-aminotyrosine,    3-chlorotyrosine, 3,5-dibromotyrosine, 3,5-diiodotyrosine,    homotyrosine, 3-iodotyrosine, 3-nitrotyrosine, 2-tyrosine,    3-tyrosine, 4-hydroxy-3-nitrophenylalanine, 5-hydroxytryptophan,    3-nitro-4-hydroxyphenylalanine, thyronine,    3,4-dihydroxyphenylalanine, 4-hydroxyphenylglycine, 3-aminosalicylic    acid; 4-aminosalicylic acid; and 5-aminosalicylic acid.

E2. Absorbable Isocyanates of Formula B:

Wherein:

-   Each X is independently selected from:-   —OCH₂CO— (glycolic ester moiety)-   —OCH(CH₃)CO— (lactic ester moiety)-   —OCH₂CH₂OCH₂CO— (dioxanone ester moiety)-   —OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone ester moiety);-   —O(CH₂)_(y)CO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —O(CH₂CH₂O)_(m)CH₂CO—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   Each X′ is independently selected from:-   —CH₂COO— (glycolic moiety)-   —CH(CH₃)COO— (lactic moiety)-   —CH₂CH₂OCH₂COO— (dioxanone moiety)-   —CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety)-   —(CH₂)_(y)COO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —(CH₂CH₂O)_(m)CH₂COO—; where m is integer between 2-24 inclusive;    and,-   R is a residue of an amino acid including but not limited to    alanine, asparagine, aspartic acid, gamma amino butyric acid,    glycine, glutamic acid, valine, lysine, isoleucine, leucine,    tyrosine, ornithine, phenylalanine and sarcosine, 3-aminotyrosine,    3-chlorotyrosine, 3,5-dibromotyrosine, 3,5-diiodotyrosine,    homotyrosine, 3-iodotyrosine, 3-nitrotyrosine, 2-tyrosine,    3-tyrosine, 4-hydroxy-3-nitrophenylalanine, 5-hydroxytryptophan,    3-nitro-4-hydroxyphenylalanine, thyronine,    3,4-dihydroxyphenylalanine, 4-hydroxyphenylglycine, 3-aminosalicylic    acid; 4-aminosalicylic acid; and 5-aminosalicylic acid.

E3. Absorbable Amines of Formula C

Wherein

-   Each X′ is independently selected from:-   —CH₂COO— (glycolic moiety)-   —CH(CH₃)COO— (lactic moiety)-   —CH₂CH₂OCH₂COO— (dioxanone moiety)-   —CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety)-   —(CH₂)_(y)COO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —(CH₂CH₂O)_(m)CH₂COO—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   R is a residue of an amino acid including but not limited to    alanine, asparagine, aspartic acid, gamma amino butyric acid,    glycine, glutamic acid, valine, lysine, isoleucine, leucine,    tyrosine, ornithine, phenylalanine and sarcosine, 3-aminotyrosine,    3-chlorotyrosine, -nitrotyrosine, 2-tyrosine, 3-tyrosine,    4-hydroxy-3-nitrophenylalanine, 5-hydroxytryptophan,    3-nitro-4-hydroxyphenylalanine, thyronine,    3,4-dihydroxyphenylalanine, 4-hydroxyphenylglycine, 3-aminosalicylic    acid; 4-aminosalicylic acid; and 5-aminosalicylic acid.

E4. Absorbable Isocyanates of Formula D

Wherein

-   Each X′ is independently selected from-   —CH₂COO— (glycolic moiety)-   —CH(CH₃)COO— (lactic moiety)-   —CH₂CH₂OCH₂COO— (dioxanone moiety)-   —CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety)-   (CH₂)_(y)COO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —(CH₂CH₂O)_(m)CH₂COO—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   R is a residue of an amino acid including but not limited to    alanine, asparagine, aspartic acid, gamma amino butyric acid,    glycine, glutamic acid, valine, lysine, isoleucine, leucine,    tyrosine, ornithine, phenylalanine and sarcosine, 3-aminotyrosine,    3-chlorotyrosine, 3,5-dibromotyrosine, 3,5-diiodotyrosine,    homotyrosine, 3-iodotyrosine, 3-nitrotyrosine, 2-tyrosine,    3-tyrosine, 4-hydroxy-3-nitrophenylalanine, 5-hydroxytryptophan,    3-nitro-4-hydroxyphenylalanine, thyronine,    3,4-dihydroxyphenylalanine, 4-hydroxyphenylglycine, 3-aminosalicylic    acid; 4-aminosalicylic acid; and 5-aminosalicylic acid.

E5. Absorbable Amines of Formula E

Wherein:

-   Each X is independently selected from:-   —OCH₂CO— (glycolic ester moiety)-   —OCH(CH₃)CO— (lactic ester moiety)-   —OCH₂CH₂OCH₂CO— (dioxanone ester moiety)-   —OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone ester moiety);-   —O(CH₂)_(y)CO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —O(CH₂CH₂O)_(m)CH₂CO—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   Each Y is independently selected from:-   —COCH₂O— (glycolic moiety)-   —COCH(CH₃)O— (lactic moiety)-   —COCH₂OCH₂CH₂O— (dioxanone moiety)-   —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone moiety)-   —CO(CH₂)_(y)O— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —CO(CH₂CH₂O)_(m)CH₂O—; where m is integer between 2-24 inclusive;    and,-   R is a residue of an amino acid including but not limited to    alanine, asparagine, aspartic acid, gamma amino butyric acid,    glycine, glutamic acid, valine, lysine, isoleucine, leucine,    tyrosine, ornithine, phenylalanine and sarcosine, 3-aminotyrosine,    3-chlorotyrosine, 3,5-dibromotyrosine, 3,5-diiodotyrosine,    homotyrosine, 3-iodotyrosine, 3-nitrotyrosine, 2-tyrosine,    3-tyrosine, 4-hydroxy-3-nitrophenylalanine, 5-hydroxytryptophan,    3-nitro-4-hydroxyphenylalanine, thyronine,    3,4-dihydroxyphenylalanine, 4-hydroxyphenylglycine, 3-aminosalicylic    acid; 4-aminosalicylic acid; and 5-aminosalicylic acid, and-   R′ is a residue of a diol where in R′ is alkyl or aryl, arylalkyl,    with alkyl chains containing a primary (long) chain of 2 up to 24    chain atoms, or alkyl substituted with analogs in which primary    chain —CH₂— groups may be substituted with —O—, or —S—, and wherein    the primary chain and aryl can be substituted with lower alkyl    group(s).

E6. Absorbable Isocyanates of Formula F

Wherein:

-   Each X is independently selected from:-   —OCH₂CO—(glycolic ester moiety)-   —OCH(CH₃)CO—(lactic ester moiety)-   —OCH₂CH₂OCH₂CO—(dioxanone ester moiety)-   —OCH₂CH₂CH₂CH₂CH₂CO—(caprolactone ester moiety);-   —O(CH₂)_(y)CO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —O(CH₂CH₂O)_(m)CH₂CO—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   Each Y is independently selected from:-   —COCH₂O— (glycolic moiety)-   —COCH(CH₃)O— (lactic moiety)-   —COCH₂OCH₂CH₂O— (dioxanone moiety)-   —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone moiety)-   —CO(CH₂)_(y)O— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —CO(CH₂CH₂O)_(m)CH₂O—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   R is a residue of an amino acid including but not limited to    alanine, asparagine, aspartic acid, gamma amino butyric acid,    glycine, glutamic acid, valine, lysine, isoleucine, leucine,    tyrosine, ornithine, phenylalanine and sarcosine, 3-aminotyrosine,    3-chlorotyrosine, 3,5-dibromotyrosine, 3,5-diiodotyrosine,    homotyrosine, 3-iodotyrosine, 3-nitrotyrosine, 2-tyrosine,    3-tyrosine, 4-hydroxy-3-nitrophenylalanine, 5-hydroxytryptophan,    3-nitro-4-hydroxyphenylalanine, thyronine,    3,4-dihydroxyphenylalanine, 4-hydroxyphenylglycine, 3-aminosalicylic    acid; 4-aminosalicylic acid; and 5-aminosalicylic acid, and-   R′ is a residue of a diol where in R′ is alkyl or aryl, arylalkyl,    with alkyl chains containing a primary (long) chain of 2 up to 24    chain atoms, or alkyl substituted with analogs in which primary    chain —CH₂— groups may be substituted with —O—, or —S—, and wherein    the primary chain and aryl can be substituted with lower alkyl    group(s)

E7. Absorbable Amines Derived from Nitrophenylalanine of the Formula G:

Wherein:

-   Each Y is independently selected from:-   —COCH₂O— (glycolic moiety)-   —COCH(CH₃)O— (lactic moiety)-   —COCH₂OCH₂CH₂O— (dioxanone moiety)-   —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone moiety)-   —CO(CH₂)_(y)O— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —CO(CH₂CH₂O)_(m)CH₂O—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   R″ is alkyl or aryl, arylalkyl, with alkyl chains containing a    primary (long) chain up to 36 chain atoms (not including H), or    alkyl substituted with analogs in which primary chain —CH₂— groups    may be substituted with —O—, or —S— or ester groups, such as low    mol.wt. polyesters or polyethers, and wherein the primary chain and    aryl can be substituted with lower alkyl group(s), or R″ is a    biologically active substance.

E8. Absorbable Isocyanates Derived from Nitrophenylalanine of theFormula (H)

Wherein:

-   Each Y is independently selected from:-   —COCH₂O— (glycolic moiety)-   —COCH(CH₃)O— (lactic moiety)-   —COCH₂OCH₂CH₂O— (dioxanone moiety)-   —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone moiety)-   —CO(CH₂)_(y)O— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —CO(CH₂CH₂O)_(m)CH₂O—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   R″ is alkyl or aryl, arylalkyl, with alkyl chains containing a    primary (long) chain up to 36 chain atoms (not including H), or    alkyl substituted with analogs in which primary chain —CH₂— groups    may be substituted with —O—, or —S— or ester groups, such as low    mol.wt. polyesters or polyethers, and wherein the primary chain and    aryl can be substituted with lower alkyl group(s), or R″ is a    biologically active substance.

E9. Absorbable Amines Derived from Nitrophenylalanine of the Formula I:

Wherein:

-   Each X is independently selected from:-   —OCH₂CO—(glycolic ester moiety)-   —OCH(CH₃)CO—(lactic ester moiety)-   —OCH₂CH₂OCH₂CO—(dioxanone ester moiety)-   —OCH₂CH₂CH₂CH₂CH₂CO—(caprolactone ester moiety);-   —O(CH₂)_(y)CO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —O(CH₂CH₂O)_(m)CH₂CO—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   Each Y is independently selected from:-   —COCH₂O— (glycolic moiety)-   —COCH(CH₃)O— (lactic moiety)-   —COCH₂OCH₂CH₂O— (dioxanone moiety)-   —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone moiety)-   —CO(CH₂)_(y)O— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —CO(CH₂CH₂O)_(m)CH₂O—; where m is integer between 2-24 inclusive.

E10. Absorbable Isocyanates Derived from Nitrophenylalanine of theFormula J:

Wherein:

-   Each X is independently selected from:-   —OCH₂CO— (glycolic ester moiety)-   —OCH(CH₃)CO— (lactic ester moiety)-   —OCH₂CH₂OCH₂CO— (dioxanone ester moiety)-   —OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone ester moiety);-   —O(CH₂)_(y)CO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —O(CH₂CH₂O)_(m)CH₂CO—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   Each Y is independently selected from:-   —COCH₂O— (glycolic moiety)-   —COCH(CH₃)O— (lactic moiety)-   —COCH₂OCH₂CH₂O— (dioxanone moiety)-   —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone moiety)-   —CO(CH₂)_(y)O— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —CO(CH₂CH₂O)_(m)CH₂O—; where m is integer between 2-24 inclusive.

E11. A Monomer or Macromer of Formula (K):

Where in

-   Each Y′ is independently selected from-   —OCOCH₂— (glycolic moiety)-   —OCOCH(CH₃)— (lactic moiety)-   —OCOCH₂OCH₂CH₂— (dioxanone moiety)-   —OCOCH₂CH₂CH₂CH₂CH₂— (caprolactone moiety)-   —OCO(CH₂)_(y)— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —OCO(CH₂CH₂O)_(m)CH₂—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   And Q′ is the residue of a diol-   Drug=Any biologically active substance containing-   —OH functional group-   —COOH functional group-   —NH₂ functional group-   R is a residue of an amino acid including but not limited to    alanine, asparagine, aspartic acid, gamma amino butyric acid,    glycine, glutamic acid, valine, lysine, isoleucine, leucine,    tyrosine, ornithine, phenylalanine and sarcosine, 3-aminotyrosine,    3-chlorotyrosine, 3,5-dibromotyrosine, 3,5-diiodotyrosine,    homotyrosine, 3-iodotyrosine, 3-nitrotyrosine, 2-tyrosine,    3-tyrosine, 4-hydroxy-3-nitrophenylalanine, 5-hydroxytryptophan,    3-nitro-4-hydroxyphenylalanine, thyronine,    3,4-dihydroxyphenylalanine, 4-hydroxyphenylglycine, 3-aminosalicylic    acid; 4-aminosalicylic acid; and 5-aminosalicylic acid.

E12. Drug and Nitric Oxide Releasing Amino Acid Monomers of Formula L:

Where in

-   Each X′ is independently selected from-   —CH₂COO— (glycolic moiety)-   CH(CH₃)COO— (lactic moiety)-   —CH₂CH₂OCH₂COO— (dioxanone moiety)-   —CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety)-   —(CH2)_(y)COO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —(CH2CH2O)_(m)CH₂COO—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   And Q′ is the residue of diol and-   Wherein-   Drug=Any bioactive substance containing-   —OH functional group-   —COOH functional group-   —NH2 functional group-   R is a residue of an amino acid including but not limited to    alanine, asparagine, aspartic acid, gamma amino butyric acid,    glycine, glutamic acid, valine, lysine, isoleucine, leucine,    tyrosine, ornithine, phenylalanine and sarcosine, 3-aminotyrosine,    3-chlorotyrosine, 3,5-dibromotyrosine, 3,5-diiodotyrosine,    homotyrosine, 3-iodotyrosine, 3-nitrotyrosine, 2-tyrosine,    3-tyrosine, 4-hydroxy-3-nitrophenylalanine, 5-hydroxytryptophan,    3-nitro-4-hydroxyphenylalanine, thyronine,    3,4-dihydroxyphenylalanine, 4-hydroxyphenylglycine, 3-aminosalicylic    acid; 4-aminosalicylic acid; and 5-aminosalicylic acid.

E13. Absorbable Amide Diacids Derived from Amino Acids and Symmetricaland Unsymmetrical Ether Acid of the Formula M:

Wherein:

-   Q is residue of symmetrical and/or unsymmetrical ether acids-   R is a residue of amino acid including but not limited to Alanine,    Asparagine, Aspartic acid, gamma amino butyric acid, glycine,    glutamic acid, valine, lysine, isoleucine, leucine, tyrosine,    ornithine, phenylalanine and sarcosine.

E14. Diisocyanate Derived from Nitrophenyl Alanine of the Formula NRespectively

Wherein

-   R″ is alkyl or aryl, arylalkyl, with alkyl chains containing a    primary (long) chain up to 36 chain atoms (not including H), or    alkyl substituted with analogs in which primary chain —CH₂— groups    may be substituted with —O—, or —S— or ester groups, such as low    mol.wt. polyesters or polyethers, and wherein the primary chain and    aryl can be substituted with lower alkyl group(s), or R″ is a    biologically active substance.-   Diisocyanate the formula N including but not limited to the    following:

E15. Absorbable Amines Derived from 3-Nitrotyrosine of the Formula P:

Wherein:

-   Each Y is independently:-   —COCH₂O— (glycolic ester moiety)-   —COCH(CH₃)O— (lactic ester moiety)-   —COCH₂OCH₂CH₂O— (dioxanone ester moiety)-   —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety)-   —OCO(CH₂)_(y)— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —OCO(CH₂CH₂O)_(m)CH₂—; where m is integer between 2-24 inclusive;-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   R″ is alkyl or aryl, arylalkyl, with alkyl chains containing a    primary (long) chain up to 36 chain atoms (not including H), or    alkyl substituted with analogs in which primary chain —CH₂— groups    may be substituted with —O—, or —S— or ester groups, such as low    mol.wt. polyesters or polyethers, and wherein the primary chain and    aryl can be substituted with lower alkyl group(s), or R″ is a    biologically active substance.

E16. Absorbable Isocyanates Derived from 3-Nitrotyrosine of the Formula(S)

Wherein:

-   Each Y is independently:-   —COCH₂O— (glycolic ester moiety)-   —COCH(CH₃)O— (lactic ester moiety)-   —COCH₂OCH₂CH₂O— (dioxanone ester moiety)-   —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety)-   —OCO(CH₂)_(y)— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —OCO(CH₂CH₂O)_(m)CH₂—; where m is integer between 2-24 inclusive;-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   R″ is alkyl or aryl, arylalkyl, with alkyl chains containing a    primary (long) chain up to 36 chain atoms (not including H), or    alkyl substituted with analogs in which primary chain —CH₂— groups    may be substituted with —O—, or —S— or ester groups, such as low    mol.wt. polyesters or polyethers, and wherein the primary chain and    aryl can be substituted with lower alkyl group(s), or R″ is a    biologically active substance.

E17. Absorbable Amines Derived from 3-Nitrotyrosine of the Formula (T):

Wherein:

-   Each X is independently:-   —OCH₂CO— (glycolic ester moiety)-   —OCH(CH₃)CO— (lactic ester moiety)-   —OCH₂CH₂OCH₂CO— (dioxanone ester moiety)-   —OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone ester moiety)-   —(CH2)_(y)COO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —(CH2CH2O)_(m)CH2COO—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   Y is independently selected from-   —COCH₂O— (glycolic moiety)-   —COCH(CH₃)O— (lactic moiety)-   —COCH₂OCH₂CH₂O— (dioxanone moiety)-   —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone moiety)-   —OCO(CH₂)_(y)— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —OCO(CH₂CH₂O)_(m)CH₂—; where m is integer between 2-24 inclusive;-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   R″ is alkyl or aryl, arylalkyl, with alkyl chains containing a    primary (long) chain up to 36 chain atoms (not including H), or    alkyl substituted with analogs in which primary chain —CH₂— groups    may be substituted with —O—, or —S— or ester groups, such as low    mol.wt. polyesters or polyethers, and wherein the primary chain and    aryl can be substituted with lower alkyl group(s), or R″ is a    biologically active substance.

E18. Absorbable Isocyanates Derived from 3-NItrotyrosine of the Formula(U):

Wherein:

-   Each X is independently:-   —OCH₂CO—(glycolic ester moiety)-   —OCH(CH₃)CO—(lactic ester moiety)-   OCH₂CH₂OCH₂CO— (dioxanone ester moiety)-   —OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone ester moiety)-   —(CH2)_(y)COO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —(CH2CH2O)_(m)CH2COO—; where m is integer between 2-24 inclusive;    and,-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   Y is independently selected from-   —COCH₂O— (glycolic moiety)-   —COCH(CH₃)O— (lactic moiety)-   —COCH₂OCH₂CH₂O— (dioxanone moiety)-   —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone moiety)-   —OCO(CH₂)_(y)— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —OCO(CH₂CH₂O)_(m)CH₂—; where m is integer between 2-24 inclusive;-   And wherein p is indepentyl selected from 0 to 6 inclusive; and,-   R″ is alkyl or aryl, arylalkyl, with alkyl chains containing a    primary (long) chain up to 36 chain atoms (not including H), or    alkyl substituted with analogs in which primary chain —CH₂— groups    may be substituted with —O—, or —S— or ester groups, such as low    mol.wt. polyesters or polyethers, and wherein the primary chain and    aryl can be substituted with lower alkyl group(s), or R″ is a    biologically active substance.

E19. A Diisocyanate Derived from 3-Nitrotyrosine of the Formula V:

Wherein

-   R″ is alkyl or aryl, arylalkyl, with alkyl chains containing a    primary (long) chain up to 36 chain atoms (not including H), or    alkyl substituted with analogs in which primary chain —CH₂— groups    may be substituted with —O—, or —S— or ester groups, such as low    mol.wt. polyesters or polyethers, and wherein the primary chain and    aryl can be substituted with lower alkyl group(s), or R″ is a    biologically active substance.

E20. Hydrolysable Amide Diacids Derived from Diamines and Symmentricaland Unsymmentrical Ether Acids of the Following Formula W:

Where in Q is a residue of symmetrical and/or unsymmetrical ether acids.

-   Rx is the residue of a diamine where in Rx is alkyl, aryl, arylalkyl    and alkyl groups containing oxygen or sulfur.

E21. An Amine or Isocyanate Derived from Nitrophenylalanine of theFormula Z or ZZ:

Wherein:

-   Each Y is independently selected from:-   —COCH₂O— (glycolic moiety)-   —COCH(CH₃)O— (lactic moiety)-   —COCH₂OCH₂CH₂O— (dioxanone moiety)-   —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone moiety)-   —CO(CH₂)_(y)O— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —CO(CH₂CH₂O)_(m)CH₂O—; where m is integer between 2-24 inclusive;-   p is independently selected from 0 to 6 inclusive;-   Each X is independently:-   —OCH₂CO— (glycolic ester moiety)-   —OCH(CH₃)CO— (lactic ester moiety)-   —OCH₂CH₂OCH₂CO— (dioxanone ester moiety)-   —OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone ester moiety)-   —(CH2)_(y)COO— or, where y is one of the numbers 2, 3, 4, and 6-24    inclusive; or-   —(CH2CH2O)_(m)CH2COO—; where m is integer between 2-24 inclusive;    and-   R′ is a residue of a diol where in R′ is alkyl, aryl or arylalkyl.

E22. A surgical article or component thereof or polymeric carriercomprising a polymer that comprises an amine, isocyanate or monomeraccording to one of the foregoing embodiments, which is a stent, stentcoating, wound covering, burn covering, foam, highly porous foams,reticulated foams, tissue engineering scaffold, film, adhesionprevention barrier, implantable medical device, controlled drug deliverysystem, suture, ligature, needle and suture combination, surgical clip,surgical staple, surgical prosthesis, textile structure, coupling, tube,support, screw, pin, bone wax formulation or an adhesion preventionbarrier.

E23. A surgical article or component thereof according to embodimentE22, wherein a biologically active agent is physically embedded ordispersed into the polymer matrix of the controlled delivery system.

E24. A surgical article or component thereof or polymeric carrier ofembodiment E22, wherein the polymer is an absorbable polyester that ispolymerized with a lactone monomer including but not limited toglycolide, lactide, c-caprolactone, trimethylene carbonate,δ-valerolactone, β-butyrolactone, morpholinedione, pivalolactone,ε-decalactone, 2,5-diketomorpholine, and p-dioxanone and combinationsthereof.

E25. A pharmaceutical composition comprising a polymeric carrier ofembodiment E22 and a drug uniformly dispersed therein.

E26. A surgical article or component thereof or polymeric carrier,comprising a polymer formed by reacting an amine of one of embodimentsE1, E3, E5, E7, E9, E11, E12, E15, E17 or E21 with an isocyanate,carboxylic acid, activated carboxylic acid, or epoxide.

E27. A surgical article or component thereof or polymeric carrier,comprising a polymer formed by reacting an isocyanate of one ofembodiments E2, E4, E6, E8, E10, E14, E16, E18, E19 or E21 with anamine, alcohol, aminoalcohol, thiol or combination thereof.

E28. A surgical article or component thereof or polymeric carrier,comprising a polymer formed by reacting a carboxylic acid of one ofembodiments E13 or E20 with an alcohol, amine or combination thereof.

The disclosures of each patent, patent application and publication citedor described in this document are hereby incorporated herein byreference, in their entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

What is claimed is:
 1. An amine of the formula G:

Wherein: (i) R″ is alkyl or aryl, arylalkyl, (ii) R″ is a biologicallyactive substance, or (iii) —OR″ is

each Y is independently selected from the following, oriented asindicated: —COCH₂O— (glycolic moiety) —COCH(CH₃)O— (lactic moiety)—COCH₂OCH₂CH₂O— (dioxanone moiety) —COCH₂CH₂CH₂CH₂CH₂O— (caprolactonemoiety) —CO(CH₂)_(y)O— where y is one of the numbers 2, 3, 4, and 6-24;or —CO(CH₂CH₂O)_(m)CH₂O—; where m is integer between 2-24 inclusive; pis independently selected from 0 to 6 inclusive, wherein at least oneoccurrence of p is >1; and each X is independently selected from thefollowing, oriented as indicated: —OCH₂CO— (glycolic ester moiety)—OCH(CH₃)CO— (lactic ester moiety) —OCH₂CH₂OCH₂CO— (dioxanone estermoiety) —OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone ester moiety) —O(CH₂)_(y)CO—where y is one of the numbers 2, 3, 4 and 6-24; or—O(CH₂CH₂O)_(m)CH₂CO—; where m is integer between 2-24 inclusive.
 2. Asurgical article or component thereof or polymeric carrier comprising apolymer made from the amine of claim 1, which is a stent, stent coating,wound covering, burn covering, foam, highly porous foams, reticulatedfoams, tissue engineering scaffold, film, adhesion prevention barrier,implantable medical device, controlled drug delivery system, suture,ligature, needle and suture combination, surgical clip, surgical staple,surgical prosthesis, textile structure, coupling, tube, support, screw,pin, bone wax formulation or an adhesion prevention barrier.
 3. Asurgical article or component thereof according to claim 2, wherein abiologically active agent is physically embedded or dispersed into thepolymer matrix of the controlled delivery system.
 4. A polymercontaining surgical article or component thereof or polymeric carrier,which is a stent, stent coating, wound covering, burn covering, foam,highly porous foams, reticulated foams, tissue engineering scaffold,film, adhesion prevention barrier, implantable medical device,controlled drug delivery system, suture, ligature, needle and suturecombination, surgical clip, surgical staple, surgical prosthesis,textile structure, coupling, tube, support, screw, pin, bone waxformulation or an adhesion prevention barrier, wherein the polymer is anabsorbable polyamide made from the amine of claim 1 that is furtherpolymerized with a lactone monomer.
 5. A pharmaceutical compositioncomprising a polymeric carrier of claim 2 and a drug uniformly dispersedtherein.
 6. A surgical article or component thereof or polymericcarrier, comprising a polymer formed by reacting an amine of claim 1with an isocyanate, carboxylic acid, activated carboxylic acid, orepoxide.
 7. An isocyanate of the formula (H):

Wherein: (i) R″ is alkyl or aryl, arylalkyl, (ii) R″ is a biologicallyactive substance, or (iii) —OR″ is

each Y is independently selected from the following, oriented asindicated: —COCH₂O— (glycolic moiety) —COCH(CH₃)O— (lactic moiety)—COCH₂OCH₂CH₂O— (dioxanone moiety) —COCH₂CH₂CH₂CH₂CH₂O— (caprolactonemoiety) —CO(CH₂)_(y)O— where y is one of the numbers 2, 3, 4, and 6-24;or —CO(CH₂CH₂O)_(m)CH₂O—; where m is integer between 2-24 inclusive; pis independently selected from 0 to 6 inclusive, wherein at least oneoccurrence of p is >1; and each X is independently selected from thefollowing, oriented as indicated: —OCH₂CO— (glycolic ester moiety)—OCH(CH₃)CO— (lactic ester moiety) —OCH₂CH₂OCH₂CO — (dioxanone estermoiety) —OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone ester moiety) —O(CH₂)_(y)CO—where y is one of the numbers 2, 3, 4, and 6-24; or—O(CH₂CH₂O)_(m)CH₂CO—; where m is integer between 2-24 inclusive.
 8. Asurgical article or component thereof or polymeric carrier comprising apolymer made from the isocyanate of claim 7, which is a stent, stentcoating, wound covering, burn covering, foam, highly porous foams,reticulated foams, tissue engineering scaffold, film, adhesionprevention barrier, implantable medical device, controlled drug deliverysystem, suture, ligature, needle and suture combination, surgical clip,surgical staple, surgical prosthesis, textile structure, coupling, tube,support, screw, pin, bone wax formulation or an adhesion preventionbarrier.
 9. A surgical article or component thereof of claim 8, whereina biologically active agent is physically embedded or dispersed into thepolymer matrix of the controlled delivery system.
 10. A polymercontaining surgical article or component thereof or polymeric carrierwhich is a stent, stent coating, wound covering, burn covering, foam,highly porous foams, reticulated foams, tissue engineering scaffold,film, adhesion prevention barrier, implantable medical device,controlled drug delivery system, suture, ligature, needle and suturecombination, surgical clip, surgical staple, surgical prosthesis,textile structure, coupling, tube, support, screw, pin, bone waxformulation or an adhesion prevention barrier, wherein the polymer is anabsorbable polyurethane made from the isocyanate of claim 7 that isfurther polymerized with a lactone monomer.
 11. A pharmaceuticalcomposition comprising a polymeric carrier of claim 8 and a druguniformly dispersed therein.
 12. A surgical article or component thereofor polymeric carrier, comprising a polymer formed by reacting anisocyanate of claim 7 with an amine, alcohol, aminoalcohol, thiol orcombination thereof.
 13. The surgical article or component thereof orpolymeric carrier of claim 2, wherein in the amine (i) R″ is alkyl oraryl, arylalkyl.
 14. The surgical article or component thereof orpolymeric carrier of claim 2, wherein in the amine (ii) R″ is abiologically active substance.
 15. The surgical article or componentthereof or polymeric carrier of claim 2, wherein in the amine (iii) —OR″is


16. The surgical article or component thereof of claim 3, wherein in theamine (i) R″ is alkyl or aryl, arylalkyl.
 17. The surgical article orcomponent thereof of claim 3, wherein in the amine (iii) —OR″ is


18. The surgical article or component thereof or polymeric carrier ofclaim 8, wherein in the isocyanate (i) R″ is alkyl or aryl, arylalkyl.19. The surgical article or component thereof or polymeric carrier ofclaim 8, wherein in the isocyanate (ii) R″ is a biologically activesubstance.
 20. The surgical article or component thereof or polymericcarrier of claim 8, wherein in the isocyanate (iii) —OR″ is


21. The surgical article or component thereof of claim 9, wherein in theisocyanate (i) R″ is alkyl or aryl, arylalkyl.
 22. The surgical articleor component thereof of claim 9, wherein in the isocyanate (iii) —OR″ is


23. The surgical article or component thereof or polymeric carrier ofclaim 8, wherein the Y includes —CO(CH₂CH₂O)_(m)CH₂O—.